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  • 1995-1999  (313)
  • 1985-1989  (1,613)
  • 1999  (313)
  • 1987  (1,613)
  • Analytical Chemistry and Spectroscopy  (1,309)
  • Atomic, Molecular and Optical Physics  (275)
  • pharmacokinetics  (182)
  • Nuclear reactions
  • breast cancer
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  • 1995-1999  (313)
  • 1985-1989  (1,613)
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Keywords
  • 1
    Electronic Resource
    Electronic Resource
    Human Interindividual Variability in Parameters Related to Health Risks (1999)
    Springer
    Risk analysis 19 (1999), S. 711-726 
    Details
    ISSN: 1539-6924
    Keywords: variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007045922532
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  • 2
    Electronic Resource
    Electronic Resource
    Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics (1999)
    Springer
    Risk analysis 19 (1999), S. 547-558 
    Details
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007017116171
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of Experimental Chemoendocrine Therapy With a Combination of a Pure Antiestrogen and 5-Fluorouracil on Human Breast Cancer Cells Implanted in Nude Mice (1999)
    Springer
    Surgery today 29 (1999), S. 149-156 
    Details
    ISSN: 1436-2813
    Keywords: Key Words: chemoendocrine therapy ; pure antiestrogen ; 5-fluorouracil ; nude mouse ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005950050376
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  • 4
    Electronic Resource
    Electronic Resource
    Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice (1999)
    Springer
    Surgery today 29 (1999), S. 149-156 
    Details
    ISSN: 1436-2813
    Keywords: chemoendocrine therapy ; pure antiestrogen ; 5-fluorouracil ; nude mouse ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The antitumor effects of an experimental chemoendocrine therapy combining a new pure antiestrogen ICI 182780 and 5-fluorouracil (5-FU) were studied on MCF-7 human breast cancer cells implanted in nude mice. ICI 182780 had a dose-dependent antitumor activity, which was potentiated by the concomitant use of 5-FU. When compared with the control group, the estrogen receptor (ER) level in the ICI 182780 group was lower and that in the combination group was markedly lower. Cell cycle analysis by flow cytometry (FCM) resulted in a lower percentage of S-phase cells (%S) in the treated mice. No significant difference was observed in the 5-FU concentrations in tumor cells, while the 5-FU content in RNA was significantly higher in the combination group. The changes in free thymidylate synthetase (TS) concentration indicated TS synthesis after the administration of 5-FU to be more greatly suppressed in the combination group than in the 5-FU group. These results suggest that ICI 182780 and 5-FU exert their combination effect mainly on ER-positive cells, and that the suppression of TS synthesis in tumor cells and the potentiation of the 5-FU-induced metabolic dysfunction of RNA are thus involved in the mode of action of this combination therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02482240
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  • 5
    Electronic Resource
    Electronic Resource
    Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older (1999)
    Springer
    Annals of oncology 10 (1999), S. 397-402 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; old age ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Older patients with advanced breast cancer are less likely to receive chemotherapy than younger patients. Vinorelbine is an attractive alternative in this setting because of its clinical activity and low frequency of side effects. This multicenter, phase II trial was designed to assess the safety and efficacy of intravenous vinorelbine as first-line therapy in women ≥60 years old. Patients and methods: Fifty-six women (median age, 72 years; range 60–84 years), with measurable advanced breast cancer and no prior chemotherapy for metastatic disease, were enrolled and included in the analysis. Vinorelbine 30 mg/m2 was administered weekly for 13 weeks and then every two weeks until development of progressive disease; doses were reduced or delayed to manage toxicity. Results: The objective response rate was 38% (95% confidence interval (95% CI): 24%–51%); median duration of response, nine months; median time to disease progression in all patients, six months. The major dose-limiting toxicity was hematologic, which led to a median dose intensity of 20.6 mg/m2/week. Grade 3–4 nonhematologic toxicity consisted of asthenia (7%); nausea and generalized pain (5%); vomiting, chest pain, abdominal pain, and elevated AST (4%); fever, diarrhea, constipation, and injection site reaction (2%). Neurotoxicity and alopecia were grade 1–2 and relatively infrequent. Conclusions: Vinorelbine offers a promising alternative for the management of advanced breast cancer in elderly patients who are concerned about the subjective side effects of cytotoxic chemotherapy. The dose-limiting toxicity is neutropenia, which is readily managed with dose adjustment. Nonhematologic toxicity, including gastrointestinal side effects, is minimal. Randomized studies are warranted to compare the activity of vinorelbine with that of other regimens in elderly patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008364222793
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors (1999)
    Springer
    Annals of oncology 10 (1999), S. 441-448 
    Details
    ISSN: 1569-8041
    Keywords: cisplatin ; dFdCTP accumulation ; gemcitabine ; pharmacodynamics ; pharmacokinetics ; phase I study ; Pt-DNA adducts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To determine possible schedule dependent pharmacokinetic and pharmacodynamic interactions between gemcitabine (2′,2′-difluorodeoxycytidine, dFdC) and cisplatin (cis-diamminedichloroplatinum, CDDP) in patients with advanced stage solid tumors in a phase I trial. Patients and methods: A total of 33 patients with advanced stage solid tumors were treated with gemcitabine (30-min infusion, 800 mg/m2) and cisplatin (one-hour infusion, 50 mg/m2). Sixteen patients had a four-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 1 and 8), followed by the reverse schedule and seventeen patients had a 24-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 2 and 9), followed by the reverse schedule. Gemcitabine and cisplatin pharmacokinetics were measured in plasma and white blood cells (WBC), isolated from blood samples taken at several time points after the start of treatment. Results: A four-hour time interval between both agents did not reveal major differences in plasma pharmacokinetics of gemcitabine, dFdU (deaminated gemcitabine) and platinum (Pt), and of gemcitabine–triphosphate (dFdCTP) accumulation and Pt-DNA adduct formation in WBC between the two different sequences of gemcitabine and cisplatin. In the patients treated with the 24-hour interval, cisplatin before gemcitabine did not significantly change peak gemcitabine levels and the AUC of plasma dFdU, but tended to increase dFdCTP AUC in WBC 1.5-fold (P 〈 0.06). Gemcitabine before cisplatin decreased the plasma AUC of Pt 2.1-fold (P = 0.03). No significant differences in Pt-DNA adduct levels in WBC were found, although gemcitabine before cisplatin tended to increase the 24-hour retention of Pt-DNA adducts. Creatinine clearance on day 28 was related to the peak plasma levels of total Pt (linear regression coefficient (r) = 0.47, P = 0.02, n = 26). Furthermore, the increase in the Pt-GG to Pt-AG ratio 24 hours after cisplatin treatment was related to the overall response of patients (r = 0.89, P 〈 0.01, n = 8). Conclusions: Of all schedules the treatment of patients with cisplatin 24 hours before gemcitabine led to the highest dFdCTP accumulation in WBC and total Pt levels in plasma. These characteristics formed the basis for further investigation of this schedule in a phase II clinical study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008301522349
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  • 7
    Electronic Resource
    Electronic Resource
    Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival (1999)
    Springer
    Annals of oncology 10 (1999), S. 707-713 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; fibroblast growth factor ; microvasculature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Angiogenesis, the process whereby endothelial cells divide and migrate to form new blood capillaries, has been assessed in tumours by measuring microvessel density. High microvessel density is a significant adverse prognostic factor in breast cancer. The angiogenic factor, basic fibroblast growth factor (bFGF), has been associated with tumourigenesis and metastasis in several human cancers. There are few quantitative studies of bFGF expression in normal tissues compared to cancer. Patients and methods: We have measured bFGF levels in 149 human primary breast carcinomas and assessed the findings in relation to microvessel density, oestrogen receptor (ER) and epidermal growth factor receptor (EGFR). Basic FGF levels were measured by ELISA. Western blotting and immunohistochemistry were carreid out to confirm the presence of bFGF. Results: Levels of bFGF were more than 10-fold higher in tumour cytosols compared to reduction mammoplasty tissue and 3-fold compared to non neoplastic cytosols from the same breast as the tumour (P 〈 0.0001). Immunohistochemistry showed bFGF protein was localised exclusively in the stroma whereas no bFGF staining was observed in the epithelial cells. High bFGF levels were significantly related to high ER (P = 0.01). Similarly, high bFGF levels were significantly related to low grade (P = 0.046) and to small tumour size (P = 0.04). No significant relationship was observed between bFGF and microvessel count, EGFR or age. In univariate analysis and in a Cox proportional hazard model bFGF did not reach significance for overall or relapse free survival. Conclusions: Our results show that although bFGF is elevated in breast carcinomas compared to normal breast tissue it is not related to microvessel density and it is not an independent predictor of survival in breast cancer patients. Basic FGF may be one of multiple factors that synergise with other growth factors such as VEGF to enhance angiogenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008303614441
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  • 8
    Electronic Resource
    Electronic Resource
    ESTIC position paper: High-dose chemotherapy for breast cancer, investigation should continue (1999)
    Springer
    Annals of oncology 10 (1999), S. 903-905 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; high-dose chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008396811371
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  • 9
    Electronic Resource
    Electronic Resource
    The influence of familial and hereditary factors on the prognosis of breast cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 1163-1170 
    Details
    ISSN: 1569-8041
    Keywords: BRCA1 ; BRCA2 ; breast cancer ; family history ; survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Family history is a well recognized risk factor for breast cancer, but its impact in terms of breast cancer survival is uncertain. The recent identification of breast cancer predisposing genes has provided new clinical insights in this field. Design: English literature identified through Medline between 1976 and February 1999 was reviewed including search terms: breast cancer, survival, prognosis, family history, genetics, BRCA1, BRCA2, and related articles. Results: Publications were divided into three categories.Family history-based studies: eighteen articles were reviewed. Four studies showed a statistically significant better survival in patients with a family history of breast cancer, and two studies demonstrated a significantly worse prognosis in this context. The remaining articles showed no significant difference. Linkage studies: Two studies based on linkage to BRCA1 found that overall survival was better in linked families. A third one concluded to a worse outcome in BRCA2-linked tumors. Mutation-based studies: 10 studies looking at the association between germ-line mutations in BRCA1/BRCA2 and clinical outcomes were reviewed. Eight articles reported no significant difference in outcome, whereas two studies showed a worse outcome in patients with mutations. Conclusions: Conflicting data exist as to whether the prognosis of familial or hereditary breast cancer differs from that of sporadic cases. Some of the discrepancies may be explained by methodological differences or biases. However, no studies showed a survival advantage for BRCA1mutation carriers. This seems to indicate that BRCA1-related breast cancer is not associated with a survival advantage, and that in fact, certain BRCA1 germline mutations confer a worse prognosis. However, to adequately answer this question, more efficient molecular tools to identify all the genetic changes responsible for breast cancer predisposition, and large cohort studies to evaluate their clinical consequences, are needed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008301314812
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  • 10
    Electronic Resource
    Electronic Resource
    Local relapse in primary breast cancer patients with unexcised positive surgical margins after lumpectomy, radiotherapy and chemoendocrine therapy (1999)
    Springer
    Annals of oncology 10 (1999), S. 1451-1455 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; chemotherapy ; margins ; radiotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Inadequate surgical excision with residual involvement of resection margins by tumour after breast conservation results in increased local recurrence rates. To reduce this risk positive margins are, therefore, usually excised. Systemic treatment with tamoxifen or chemotherapy reduces local recurrence, along with radiotherapy. However, no studies to date have examined the correlation between chemoendocrine treatment, together with radiotherapy, and local relapse in patients with unexcised involved resection margins, having had breast conservation treatment. Patients and methods: The histopathology reports were reviewed of 184 patients who were treated from June 1991 to August 1995 within our randomised study of neoadjuvant versus adjuvant chemoendocrine therapy with mitozantrone and methotrexate (2M) ± mitomycin-C (3M) and tamoxifen, used concurrently with radiation following conservation surgical treatment. Histological resection margin was considered positive if ductal carcinoma in situ (DCIS) or invasive carcinoma was present microscopically less than 1mm from the excision margin. Results: Although 38% of patients had unexcised microscopically involved margins, local relapse rate as first site of relapse was only 1.9% after a median follow up of 57 months. There was no difference in distant relapse (P = 0.2) and survival (P = 0.5) between the positive and negative margins groups. Conclusions: The presence of positive unexcised margins does not have a significant effect on outcome in patients who are treated with chemoendocrine therapy together with radiotherapy. Further clinical trials are required.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008371318784
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  • 11
    Electronic Resource
    Electronic Resource
    Docetaxel in the community setting: An analysis of 377 breast cancer patients treated with docetaxel (Taxotere®) in the UK (1999)
    Springer
    Annals of oncology 10 (1999), S. 205-210 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; docetaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Given as first- or second-line chemotherapy, docetaxel appears to have great potential in advanced breast cancer. Patients and methods: Three hundred and seventy-seven locally advanced or metastatic breast cancer patients received docetaxel (Taxotere®) as part of a named patient programme under the care of 108 oncologists from 61 cancer units across the UK. The recommended starting dose was 100 mg/m2, but patients at higher risk of toxicity started at 75 mg/m2. All patients received corticosteroid premedication. The modal number of prior chemotherapy regimens was 2 (range 1–7), 342 patients (91%) had at least one prior anthracycline-based regimen. Results: Response was graded according to the managing clinician's best judgement without formal criteria. The overall response rate (ORR) was 46% among the 331 evaluable patients, 46% among the 299 patients who were 'anthracycline resistant' and 35% among the 82 patients who were 'anthracycline refractory' (progressive disease being the best response obtained to the most recent anthracycline containing regimen). One hundred and ninety-three patients started at the full dose of 100 mg/m2 with an ORR of 55% and 129 started at 75 mg/m2 with an ORR of 33%. In October 1997, some two years after the programme had started, 26 of 377 patients were still alive, although no complete remissions have lasted to this date. Kaplan–Meier survival analysis yielded a median survival of 194 days (95% CI: 178–218 days). Haematological parameters were checked before each course of docetaxel and additionally as clinically indicated. The safety data confirmed that docetaxel has a manageable, predictable side effect profile; 29 of 377 (7.7%) patients were hospitalised as a result of neutropenic sepsis. Conclusions: The results of this named patient programme over a two year timespan confirm that docetaxel is an effective chemotherapy option in patients with locally advanced and/or metastatic breast cancer, including an 'anthracycline refractory' population.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008370930599
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  • 12
    Electronic Resource
    Electronic Resource
    Phase II study of epirubicin and vinorelbine with granulocyte colony-stimulating factor: A high-activity, dose-dense weekly regimen for advanced breast cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 937-942 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; dose-intensity ; epirubicin ; G-CS/kwd〉 ; vinorelbine ; weekly schedule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: This study was designed to explore the effectiveness and tolerability of a weekly regimen of epirubicin and vinorelbine plus granulocyte colony-stimulating factor (G-CSF). Patients and methods: Fifty-two patients with previously untreated advanced breast cancer were treated with epirubicin (25 mg/m2/week) and vinorelbine (25 mg/m2/week) with G-CSF support, for 24 consecutive weeks. Results: The median number of courses per patient was 22 (range 10–24). The administered dose intensity was 23 mg/m2 for both epirubicin and vinorelbine. Ten complete responses (19%) and 30 partial responses (58%) were obtained, for an overall response rate of 77%. None of the patients progressed during treatment. The median response duration and time to progression were both 10 months. A total of 1065 courses were assessed for toxicity. Grade 3 neutropenia was the most common toxic manifestation, (39% of patients), without febrile neutropenia or neutropenic sepsis. Two patients had grade 3 cardiac toxicity, which regressed without sequelae. Median survival was 31 months, with a median follow-up of 24 months (range 9–40). Conclusions: Owing to its effectiveness and tolerability, the weekly regimen of epirubicin and vinorelbine plus G-CSF may represent an acceptable alternative for patients with untreated metastatic breast cancer. It could be tested in the adjuvant and neoadjuvant setting.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008324329562
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  • 13
    Electronic Resource
    Electronic Resource
    Paclitaxel by 24-hour infusion with doxorubicin by 48-hour infusion as initial therapy for metastatic breast cancer: Phase I results (1999)
    Springer
    Annals of oncology 10 (1999), S. 403-411 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; doxorubicin ; paclitaxel-anthracycline combination ; schedule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: We and others have demonstrated the antineoplastic efficacy of paclitaxel as a single agent in metastatic breast cancer. We performed this phase I trial to evaluate the combination of paclitaxel with doxorubicin. Patients and methods: Eligible patients had measurable or evaluable metastatic breast cancer for which this was the initial cytotoxic treatment. They may have received adjuvant chemotherapy with other drugs. The study had four parts. In part 1, the patients received paclitaxel by 24-hour infusion followed by doxorubicin by 48-hour infusion. The paclitaxel dose was to be escalated from a starting dose of 125 mg/m2, and the doxorubicin dose was to remain constant at 60 mg/m2 with treatment repeated every three weeks. The results of part 1 prompted part 2 which was a study of the reverse sequence. Part 3 was a formal study of pharmacology and has been reported (J Clin Oncol 14: 2713–21, 1996). In part 4, patients received doxorubicin 50 mg/m2 by bolus followed by paclitaxel 150 mg/m2 by 24-hour infusion for courses 1 and 2. In all subsequent courses doxorubicin was administered by 48-hour infusion. All patients in all four parts of the study had baseline cardiac scans. All patients received standard premedication for paclitaxel. Results: Forty-eight patients were treated in all four parts of the study. In part 1 (10 patients), the maximum tolerated dose (MTD) was paclitaxel 125 mg/m2/24 hours followed by doxorubicin 48 mg/m2/48 hours as defined by dose-limiting mucositis and neutropenic fever which occurred at the starting dose. For part 2 (21 patients), the MTD was doxorubicin 60 mg/m2/48 hours followed by paclitaxel 160 mg/m2/24 hours. In part 4 (seven patients), the MTD was doxorubicin 50 mg/m2/bolus followed by paclitaxel 135 mg/m2/24 hours. In parts 2 and 4, the dose-limiting toxic effect was neutropenia. Of the entire cohort of 48 patients, seven (15%) had a complete response (one persists at five years without intervening therapy), 26 (54%) had a partial response for an objective response rate of 69% (95% confidence interval (95% CI): 54%–81%). The median follow-up of all living patients is 38+ months (range 20+ to 62+); the median response duration is seven months (range 2–33.7+); the median overall survival is 20.5 months (range 5–54+). The median time to progression is 9.6 months (range 1–33.7+ months). Two patients developed congestive heart failure, one at 24 months after her final dose of doxorubicin which amounted to a cumulative lifetime total doxorubicin dose of 870 mg/m2, one after a total of 660 mg/m2. In both, cardiac symptoms were controlled with medications. Conclusions: The combination of paclitaxel/24 hours with doxorubicin/48 hours is an effective antineoplastic treatment for metastatic breast cancer. However, the incidence of complete response, the median overall survival, and time to progression were not greater than for standard doxorubicin-based combinations. Additionally, a sequence-dependent interaction between paclitaxel and doxorubicin, given in the schedule described here, was defined. Other strategies and schedules should be evaluated to maximize the antineoplastic efficacy of these two potent agents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008360406322
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  • 14
    Electronic Resource
    Electronic Resource
    Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours (1999)
    Springer
    Annals of oncology 10 (1999), S. 831-838 
    Details
    ISSN: 1569-8041
    Keywords: melanoma ; pharmacodynamics ; pharmacokinetics ; temozolomide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. Patients and methods: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. Results: The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. Conclusions: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008304032421
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  • 15
    Electronic Resource
    Electronic Resource
    Primary chemotherapy in operable breast cancer with favorable prognostic factors: A pilot study evaluating the efficacy of a regimen with a low subjective toxic burden containing vinorelbine, 5-fluorouracil and folinic acid (FLN) (1999)
    Springer
    Annals of oncology 10 (1999), S. 993-996 
    Details
    ISSN: 1569-8041
    Keywords: 5-fluorouracil ; breast cancer ; neoadjuvant ; primary chemotherapy ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Biological considerations support the use of primary chemotherapy in operable breast cancer; and despite wide variations of used regimens, clinical studies consistently show a significant tumor response allowing breast conservation in many patients otherwise canditates for mastectomy. We investigated the efficacy and the acceptance of a combination chemotherapy with vinorelbine, 5-fluorouracil and high-dose folinic acid in operable breast cancer with favorable prognostic factors and tested the relationship of hormone receptor status, Ki67, p53, c-erbB2 and bcl-2 with treatment response. Patients and methods: Thirty-nine patients (median age 51 years, range 36–71 years), eight with T1, twenty-eight with T2 and two with T3 lesions, were treated with 5-fluorouracil (350 mg/m2, i.v. on day 1 to 3) preceded by folinic acid (100 mg/m2 i.v. on day 1 to 3) and vinorelbine, given on days 1 and 3 at the dose of 20 mg/m2 (FLN regimen). Therapy was administered on an outpatient basis every three weeks. Non responders had surgery after three courses, while complete or partial responders underwent surgery after six courses. All but one were evaluable for response and toxicity. Results: Objective responses were observed in 23 of the 38 evaluable patients (61%; 95% CI: 46%–76%): three complete responses (8%) and 20 partial responses (53%). Fifteen patients (39%) had stable disease, of whom nine (23%) had minor response. None of the patients had disease progression during treatment. Objective responses were significantly associated with no expression of estrogen and/or progesteron receptors and 〉50% decrease in Ki67 after induction chemotherapy. Tolerance was excellent and none of the patients experienced grade 2 alopecia. Conclusions: The ‘moderate’ efficacy of this regimen might be partially due to the selection of patients with high expression of steroid hormone receptors and low proliferation rate, which have an unfavorable impact on response to this chemotherapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008389106575
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  • 16
    Electronic Resource
    Electronic Resource
    Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 53-58 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; cardiotoxicity ; cyclophosphamide ; epirubicin ; high dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To prospectively evaluate the long term cardiac effects of high-dose epirubicin and cyclophosphamide given to women with early stage, poor prognosis breast cancer. Patients and methods: Women with stage 2 breast cancer and 10+ nodes or 4+ nodes and estrogen receptor negative tumor, or stage 3 breast cancer received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 gm/m2 with peripheral blood progenitor cell and filgrastim support. Treatment was given every 28 days (n = 79) or 21 days (n = 20). Fifty patients received radiotherapy to the chest wall or breast, 25 of to the left side. Patients were assessed clinically regularly during chemotherapy and at least three times yearly after completion of treatment. Cardiac left ventricular ejection fraction (LVEF) was assessed by radionuclide scan before therapy, after each cycle of chemotherapy, three months and six months after completion of chemotherapy, and yearly thereafter until relapse. Results: Ninety-nine women were treated, and 92 completed all three cycles of chemotherapy. The median age was 43 years (range 24 to 60 years). All patients were included in this analysis. The median relapse-free survival was 39 months (11 to 68 months). There was a significant fall in LVEF during chemotherapy. In general, there was no further deterioration in cardiac function from the third month after cessation of treatment, however there was substantial variation between individuals. 35 patients had at least one LVEF measure less than normal (〈50%), but the LVEF returned to normal in 20 of these with further follow-up. Cardiac dysfunction was not increased in women who received radiotherapy and was not different between cohorts given chemotherapy every three or every four weeks. One patient died of acute myocardial necrosis following the third cycle of chemotherapy. Two patients developed clinical evidence of cardiac failure, and another had radiological signs but was asymptomatic. One woman died of progressive cardiac failure, one recovered clinically but also developed recurrent breast cancer, while the third recovered after commencement of medical therapy. Conclusions: During follow-up after high-dose epirubicin and cyclophosphamide as delivered in this study, the LVEF fell to below normal in approximately one third of patients. However, in over half of these patients the LVEF subsequently recovered to the normal range, and the incidence of clinically evident chronic cardiac failure was low. Further follow-up is required to assess the long- term safety. A randomized comparison with standard-dose anthracycline-based chemotherapy is needed to determine whether this regimen is associated with an increased risk of clinical cardiac toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008390203340
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  • 17
    Electronic Resource
    Electronic Resource
    Breast cancer screening by mammography in Norway. Is it cost- effective? (1999)
    Springer
    Annals of oncology 10 (1999), S. 197-203 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; cost-effectiveness ; mammography ; screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Mammography screening is a promising method for improving prognosis in breast cancer. Patients and methods: In this economic analysis, data from the Norwegian Mammography Project (NMP), the National Health Administration (NMA) and the Norwegian Medical Association (NMA) were employed in a model for cost-effectiveness analysis. According to the annual report of the NMP for 1996, 60,147 women aged 50–69 years had been invited to a two-yearly mammographic screening programme. 46,329 (77%) had been screened and 337 (0.7%) breast cancers had been revealed. The use of breast conserving surgery (BCS) was in this study estimated raised by 17% due to screening, the breast cancer mortality decreased by 30% and the number of life years saved per prevented breast cancer death was calculated 15 years. Results: The cost per woman screened was calculated £75.4, the cost per cancer detected £10,365 and the cost per life year (LY) saved £8,561. A raised frequency of BCS, diagnosis and adjuvant chemotherapy brought two years forward, follow-up costs and costs/savings due to prevented breast cancer deaths were all included in the analysis. A sensitivity analysis documented mammography screening cost-effective in Norway when four to nine years are gained per prevented breast cancer death. Conclusion: Mammography screening in Norway looks cost- effective. Time has come to encourage national screening programmes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008376608270
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  • 18
    Electronic Resource
    Electronic Resource
    The third-generation non-steroidal aromatase inhibitors: A review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 377-384 
    Details
    ISSN: 1569-8041
    Keywords: anastrozole ; aromatase inhibitors ; breast cancer ; hormonal therapy ; letrozole ; review ; vorozole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three new aromatase inhibitors have recently completed phase III evaluation as treatment of metastatic breast cancer in post-menopausal women whose disease has progressed despite tamoxifen therapy: anastrozole (ARIMIDEX, Zeneca), letrozole (FEMARA, Novartis) and vorozole (RIVIZOR, Janssen). All belong to the third generation of non-steroidal aromatase inhibitors, and each is superior to previous generations in terms of potency and selectivity. The trials that have been performed compare each agent to megestrol acetate, and letrozole and vorozole to aminoglutethimide. Although the studies are not directly comparable due to differing study designs and patient populations, it has been demonstrated each of these drugs provides single agent, once-daily, oral palliation of hormone-responsive, post-menopausal metastatic breast cancer. Letrozole is clearly more effective than megestrol acetate, and anastrozole and vorozole are possibly so. All three are better tolerated than the progestin, particularly in terms of weight gain. Both letrozole and vorozole are significantly more effective, and better tolerated than aminoglutethimide. Overall, this most recent generation of aromatase inhibitors is a clear improvement on our current standard second-line therapies. In 1999, tamoxifen remains the first choice in the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal second-line hormonal therapy remains undefined, but aminoglutethimide and megestrol acetate are no longer optimal therapy in this setting. The third-generation non-steroidal aromatase inhibitors must now be compared to each other, to the steroidal aromatase inhibitors, to the pure anti-oestrogens, and to tamoxifen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008368300827
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  • 19
    Electronic Resource
    Electronic Resource
    Synchronous inflammatory breast cancer and advanced ovarian carcinoma: A case with prolonged disease-free survival (1999)
    Springer
    Annals of oncology 10 (1999), S. 585-588 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; cisplatin ; ovarian cancer ; paclitaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Despite the known association of these malignancies, the incidence of a synchronous presentation of breast and ovarian cancer is low, and the current literature does not address an approach to this clinical problem directly. We report a greater than 2.5 year disease-free survival in a patient treated for synchronous stage IIIB inflammatory breast cancer and stage IIIC epithelial ovarian cancer. The prolonged disease-free survival in our case may provide some guidance in this unusual clinical situation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008239124657
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  • 20
    Electronic Resource
    Electronic Resource
    Autologous stem-cell transplant after conventional dose adjuvant chemotherapy for high-risk breast cancer: Impact on the delivery of local-regional radiation therapy (1999)
    Springer
    Annals of oncology 10 (1999), S. 929-936 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; local regional therapy ; stem-cell transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: High-dose chemotherapy with autologous stem-cell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy. Patients and methods: Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients. Results: Overall and disease-free survival rates at 18 months were 83% (± 4%) and 77% (± 4%) respectively. Twenty patients (19.4%) received radiation therapy prior to transplant. Of the remaining 83, 77 received radiation therapy after transplant. Overall, 5 (19.2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%–80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%–24.5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation. Conclusion: Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008393204854
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  • 21
    Electronic Resource
    Electronic Resource
    Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: Effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels (1999)
    Springer
    Annals of oncology 10 (1999), S. 329-334 
    Details
    ISSN: 1569-8041
    Keywords: carboplatin ; drug-target interaction ; ovarian cancer ; pharmacokinetically based dosing ; pharmacokinetics ; platinum-DNA adducts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Platinum based drugs are active agents in epithelial ovarian cancer and increased platinum drug dose intensity is thought to lead to improved survival, because of the largely untested assumption that increased dose intensity results in an increased interaction of the platinum drug with its target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol 1996; 14: 800–5), carboplatin dose intensity was increased by the use of G-CSF to support the bone marrow and using pharmacokinetically-guided carboplatin dosing. The objectives of this study were to validate the carboplatin dosing formula during high dose intensity therapy and evaluate the relationship between systemic carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes. Patients and methods: A total of 17 patients were studied over four levels of dose intensification. The carboplatin dose was calculated using the ‘Calvert formula’. Levels of drug-target interaction in peripheral blood leukocytes were measured using an immunoassay based on a monoclonal antibody that recognises DNA-platinum adducts. Pharmacokinetic measurements were carried out using a previously validated single sample method. Results: The area under the curve of concentration of unbound carboplatin in plasma versus time (AUC) for target AUC values of 5, 7 and 9 mg/ml·min were: 5.6 ± 1.0, 7.3 ± 0.7 and 9.8 ± 0.5 mg/ml·min (mean ± S.D.). There was a good correlation between target and achieved dose intensities (r2 = 0.899) and the slope of the linear regression line was 0.95 (± 0.09 SD) not significantly different to 1.0 (P 〉 0.6). The levels of immunoreactive DNA adducts were not detectable at a target AUC of 5 mg/ml·min but increased progressively at the higher AUC levels. Accumulation of adducts between courses was not detected. Conclusions: Pharmacokinetically-based carboplatin dosing during high intensity therapy accurately predicted the dose required to achieve a target AUC and resulted in consistent patient exposure to active drug. During the dose escalation study, peripheral blood leucocyte DNA platinum-DNA adduct levels were positively related to drug dose and drug AUC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008355506863
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  • 22
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of interleukin-2 in two anephric patients with metastatic renal cell cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 1381-1383 
    Details
    ISSN: 1569-8041
    Keywords: (adeno)carcinoma ; interleukin-2 ; kidney neoplasms ; nephrectomy ; pharmacokinetics ; renal cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Most patients with metastatic renal cell carcinoma (RCC) have undergone unilateral- and some bilateral nephrectomy. Because interleukin-2 (IL-2) is thought to be mainly cleared via the kidneys, we investigated whether IL-2 treatment is safe in anephric patients. Patients and methods: The pharmacokinetics of i.v. bolus, i.v. infusion and s.c. recombinant IL-2 were investigated in two anephric patients with progressive metastatic RCC. Results: Following i.v. bolus administration of IL-2, plasma half-lives of 126 and 84 minutes respectively, and plasma clearances of 151 ml/min and 273 ml/min respectively, were measured in the two patients. In one patient plasma clearance of IL-2 was enhanced to 760 ml/min after continuous i.v. infusion of 4 and 6 million IU IL-2/24 hours, as compared to a clearance of 310 ml/min at a dose of 2 million IU IL-2/24 hours. In the other patient, during IL-2 infusion of 2, 4 or 6 × 106 IU/24 hours, each over the course of 3 days, plasma clearance of IL-2 increased from 311 to 761, and to 687 ml/min, respectively. IL-2 could not be detected in haemo- or peritoneal dialysates. Conclusions: IL-2 plasma half-life is only moderately prolonged in anephric patients as compared to patients with normal renal function. Based on our findings, intravenous or subcutaneous treatment of anephric patients with IL-2 seems feasible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008362620308
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  • 23
    Electronic Resource
    Electronic Resource
    Adjuvant Therapy of Breast Cancer: Update (1999)
    Springer
    Annals of oncology 10 (1999), S. 129-137 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant treatment ; breast cancer ; systemic therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The theoretical prediction that breast cancer is a systemic disease, and that patients may benefit from addition of systemic therapy to local treatment, has now been confirmed by three decades of clinical investigations. A long-term follow up of individual trials and the International Overview based on meta-analyses clearly showed the potential of both hormonal therapies and chemotherapy to prolong disease-free and overall survival in nearly all groups of patients. The benefits have been demonstrated for both premenopausal and postmenopausal patients, with both node-negative and node-positive disease. However, there is still considerable uncertainty regarding the most appropriate treatment for each individual patient. In the present review, the results of meta-analysis are highlighted in the context of the new trials supporting the value of chemoendocrine therapy and anthracycline-based therapy. The results of prospective randomised trials evaluating the role of dose intensification, drug sequencing and dose density are discussed. Also presented are new treatment strategies, such as preoperative chemotherapy and high-dose chemotherapy with stem cell support, the value of which remains to be confirmed. Future possibilities opened by inclusion of biologics into adjuvant therapy are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008362521127
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  • 24
    Electronic Resource
    Electronic Resource
    New Developments in Chemotherapy of Advanced Breast Cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 139-146 
    Details
    ISSN: 1569-8041
    Keywords: anthracycline ; breast cancer ; chemotherapy ; HER-2 antibody ; N,N-diethyl-2[4-(phenylmethyl)-phenoxy] ethanamine.HCl (DPPE, BMS-217380-01) ; paclitaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Anthracyclines and taxanes are the two most active classes of chemotherapy for the treatment of advanced breast cancer. Recent studies have investigated combination therapy including doxorubicin (Dox) and paclitaxel. The efficacy of this combination has been established in a phase III study conducted by ECOG, comparing Dox/paclitaxel versus Dox versus paclitaxel. The combination is superior to Dox or paclitaxel with respect to response rate and time to disease progression, indicating that the combination provides a new standard for the first line treatment of metastatic breast cancer [1]. Phase II studies using higher doses of Dox and using shorter infusions of paclitaxel have suggested the combination can be further optimised; Gianni reported a 94% objective response rate using Dox 60 mg/m2 followed by paclitaxel 175 mg/m2 given over three hours [2]. The more active regimens are associated with enhanced cardiotoxicity; this toxicity can be avoided, however, by limiting the exposure to doxorubicin. The newer regimens have now been moved into phase III studies. Future progress for this disease will depend on the introduction of new agents. Two novel drugs are currently being investigated in randomised phase III trials as potentiators of Dox and/or paclitaxel. One is a monoclonal antibody from Genentech (Herceptin, trastuzumab) directed at the HER-2/neu oncogene, which is overexpressed in 〉25% of breast cancers [3]. Recent results indicate that Herceptin in combination with paclitaxel (or with a Dox plus cyclophosphamide regimen) induces a higher response rate (RR) and prolongs the time to disease progression when compared to chemotherapy alone. The second agent N,N-diethyl-2[4-(phenylmethyl)-phenoxyl] ethanamine.HCl (DPPE, BMS-217380-01), when combined with Dox, was associated with a higher RR than previously observed with Dox alone [4]. A randomised trial of Dox versus Dox plus DPPE is ongoing. The possible mechanisms underlying chemo-potentiation by these agents are discussed. As new anthracycline/taxane combinations establish themselves in earlier stages of the disease, the need for effective, non-cross resistant salvage regimens will emerge.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008318725670
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  • 25
    Electronic Resource
    Electronic Resource
    Cowden disease and Lhermitte Duclos disease, markers of breast carcinoma: Report of two patients (1999)
    Springer
    Annals of oncology 10 (1999), S. 1241-1243 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; Cowden disease ; Lhermitte Duclos
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008317923860
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  • 26
    Electronic Resource
    Electronic Resource
    A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex®) with intramuscular formestane in postmenopausal women with advanced breast cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 1219-1225 
    Details
    ISSN: 1569-8041
    Keywords: anastrozole ; Arimidex® ; aromatase inhibitor ; breast cancer ; formestane ; oestradiol ; tolerability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: This study provides a direct randomized comparison of a new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex®), with a steroidal aromatase inhibitor (formestane) with respect to oestrogen (oestradiol, oestrone, and oestrone sulphate) suppression and tolerability. Patients and methods: Sixty postmenopausal women with advanced breast cancer were randomized to receive either anastrozole 1 mg once daily orally (n = 29), or formestane 250 mg once every two weeks by intramuscular injection (n = 31). Treatment was continued until progression of disease or withdrawal from the study. The primary endpoints of this study were oestradiol suppression and tolerability. The secondary endpoints included oestrone and oestrone sulphate suppression. All laboratory analyses were conducted ‘blind’ of the randomized drug treatment. Results: Anastrozole produced a greater and more consistent suppression of oestradiol levels compared with formestane. Based on two- and four-week measurements, the mean fall from baseline (pre-dose) in oestradiol level was 79% and 58% in the anastrozole and formestane groups, respectively (P = 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels were also suppressed to a greater extent by anastrozole compared with formestane (oestrone: 85% versus67%, respectively, P = 0.0043; oestrone sulphate: 92% versus 67%, respectively, P = 0.0007). No statistical differences were seen between the two drugs in the incidence of adverse events. Conclusions: Anastrozole provides a more consistent and significantly more effective suppression of oestradiol compared with formestane. Similar results were observed for oestrone and oestrone sulphate. The clinical significance of these differences in total oestrogen suppression remains to be established.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008308609325
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  • 27
    Electronic Resource
    Electronic Resource
    Screening Mammography for Early Detection of Breast Cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 121-127 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; mammography ; prevention ; screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract From numerous studies on breast cancer it can be concluded that no single measure can lessen the burden of this frequent cancer in women in all developed countries. Complex strategies including primary prevention by identification of risk factors and their modification, secondary prevention by earlier detection and tertiary prevention by improving treatment outcome are needed to control the disease. Besides age, the established breast cancer risk factors include certain benign breast diseases, family history, ionising radiation, some reproductive factors and obesity. Primary prevention includes general recommendation for healthy lifestyle, e.g., avoidance of obesity, proper diet, physical activity and moderate alcohol consumption. Randomised controlled trials conducted in the USA, Canada, Scotland and Sweden have shown that regular mammography, alone or in combination with clinical examination, is effective in reducing mortality for about 30% in women over the age of 50, and much less in younger population. However, mammography screening has several drawbacks, the major being its tendency towards false positive and false negative results with all their potential psychosocial consequences. High quality assurance and control, as well as effective and readily available treatment, all of which demand high investments, are indispensable for good results. Even in the absence of organised screening, the availability of effective treatment may contribute to reduction in breast cancer mortality.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008310503380
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  • 28
    Electronic Resource
    Electronic Resource
    Cytomegalovirus pneumonia in a patient with breast cancer on chemotherapy: Case report and review of the literature (1999)
    Springer
    Annals of oncology 10 (1999), S. 461-465 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; cytomegalovirus pneumonia ; dexamethasone ; ganciclovir ; standard dose chemotherapy regimen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cytomegalovirus (CMV) pneumonia in the setting of non-transplantation patients is a rarity. We present a case of CMV pneumonitis in a woman with stage IV breast cancer, with brain metastases, receiving both chemotherapy and systemic corticosteroids. A review of the literature reveals this as a unique case. Potential viral etiologies should therefore be considered in cancer patients with pneumonia receiving non-transplantation chemotherapy-regimens, particularly if steroids are a component of their therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008360927507
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  • 29
    Electronic Resource
    Electronic Resource
    Pharmacokinetic interactions of paclitaxel, docetaxel and their vehicles with doxorubicin (1999)
    Springer
    Annals of oncology 10 (1999), S. 391-395 
    Details
    ISSN: 1569-8041
    Keywords: docetaxel ; doxorubicin ; interaction ; mice ; paclitaxel ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The combination of doxorubicin (Dx) with paclitaxel or docetaxel is clinically effective but there are concerns regarding the higher incidence of cardiotoxicity of the combination compared with Dx alone. The mechanism of the increased toxicity is still unclear. Purpose: To assess whether there is a pharmacokinetic interaction between paclitaxel, docetaxel or their vehicles and Dx in mice. Materials and methods: CDF1 male mice were treated with Dx either alone (10 mg/kg i.v.) or in combination with paclitaxel (25 mg/kg) or docetaxel (25 mg/kg) or their vehicles, i.e., cremophor-ethanol-glucose (cremophor) or polysorbate80-ethanol-glucose (polysorbate). Four mice were killed 4, 8 or 24 hours after Dx in each experimental group and Dx was assayed in serum and in heart, liver, kidney and spleen by HPLC. Results: Four hours after treatment the concentrations of Dx in heart, liver and kidney were much higher in mice concomitantly treated with paclitaxel, docetaxel (dissolved in either cremophor or polysorbate) and cremophor. At subsequent times the differences were modest and only reached statistical significance in a few cases. Dx metabolites were modified by concomitant treatment with taxanes or their vehicles. In particular, the levels of Dx aglycone in liver and kidney were significantly lower in mice treated with the combination than in mice given Dx alone. Conclusions: paclitaxel, docetaxel and cremophor when given together with Dx modify its distribution and metabolism, increasing Dx levels in many tissues including the heart. This might have some bearing on the toxicity of regimens in which Dx is combined with taxanes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008309916974
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  • 30
    Electronic Resource
    Electronic Resource
    Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: A multicenter dose-escalation study (1999)
    Springer
    Annals of oncology 10 (1999), S. 547-552 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; docetaxel ; epirubicin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To determine the maximum tolerable dose (MTD) and the dose-limiting toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients with advanced breast cancer. Patients and methods: Forty-seven chemotherapy-naïve metastatic breast cancer patients aged 〈75 years with PS (WHO) 0–2 and adequate bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with increments of 10 mg/m2; D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increments of 10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0–1, 16 (34%) were premenopausal and 25 (53%) had visceral disease. Results: When the two drugs were given on the same day, the MTD1 was reached at the doses of Epi 60 mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose intensification. When the drugs were given on two consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting events were febrile neutropenia and grade 4 neutropenia, which developed in 30 (64%) patients during the study; among 227 delivered cycles grade 3–4 neutropenia occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1–2 neurosensory toxicity occurred in nine (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%). Four (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients developed congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is considered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%–69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The median survival has not yet been reached. Conclusions: The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026441804889
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  • 31
    Electronic Resource
    Electronic Resource
    Depression in breast cancer patients: The need for treatment (1999)
    Springer
    Annals of oncology 10 (1999), S. 627-636 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; depression ; diagnosis ; treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008328005050
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  • 32
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    Electronic Resource
    A phase I study of sequential vinorelbine followed by paclitaxel (1999)
    Springer
    Annals of oncology 10 (1999), S. 861-863 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; paclitaxel ; phase I ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: In vitro experiments suggest that administration of vinorelbine preceding paclitaxel results in synergistic cytotoxic effects. A phase I dose escalation trial of vinorelbine daily × 3 with paclitaxel on day 3 repeated every 28 days in metastatic breast cancer patients was completed. Patients and methods: Female patients, PS 0–2, without evidence of CNS disease or prior neuropathies were treated with vinorelbine at dose levels 7, 10, 13 mg/m2 per day and paclitaxel over three hours at dose levels of 135, 175, and 200 mg/m2. Results: Twenty-eight patients with six dose levels were studied. At dose level 1, patients developed intolerable but reversible neutropenia. Subsequent dose levels required filgrastim. Dose limiting toxicities were myalgia and fatigue at vinorelbine 13 mg/m2 /day and paclitaxel 200 mg/m2. Neuropathy was minor. Twelve of twenty-five patients with measurable disease had a rapid response which did not correlate with dose level. Conclusions: Sequential administration of these two agents demonstrates activity in breast cancer patients. Phase II dosing on this schedule should be vinorelbine 13 mg/m2/day × 3 and paclitaxel 175 mg/m2. With proper selection of patients, concern about neurologic toxicity should not impede future trials of vinorelbine with paclitaxel.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008351915582
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  • 33
    Electronic Resource
    Electronic Resource
    Ala99ser mutation in RIα Regulatory Subunit of protein kinase A causes reduced kinase activation by cAMP and arrest of hormone-dependent breast cancer cell growth (1999)
    Springer
    Molecular and cellular biochemistry 195 (1999), S. 77-86 
    Details
    ISSN: 1573-4919
    Keywords: protein kinase A ; site-directed mutagenesis ; breast cancer ; growth arrest ; cAMP response element
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Expression of the RIα regulatory subunit of protein kinase A type I is increased in human cancer cell lines, in primary tumors, in cells after transformation, and in cells upon stimulation of growth. Ala99 (the pseudophosphorylation site) of human RIα was replaced with Ser (RIα-p) for the structure-function analysis of RIα. MCF-7 hormone- dependent breast cancer cells were transfected with an expression vector for the wild-type RIα or mutant RIα-p. Overexpression of RIα-P resulted in suppression of protein kinase A type II, the isozyme of type I kinase, production of kinase exhibiting reduced cAMP activation, and inhibition of cell growth showing an increase in G0/G1 phase of the cell cycle and apoptosis. The wild-type RIα overexpression had no effect on protein kinase A isozyme distribution or cell growth. Overexpression of protein kinase A type II regulatory subunit, RIIβ, suppressed RIα and protein kinase A type I and inhibited cell growth. These results show that the growth of hormone-dependent breast cancer cells is dependent on the functional protein kinase A type I.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006934113439
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  • 34
    Electronic Resource
    Electronic Resource
    Agonist and antagonist-induced qualitative and quantitative alterations of progesterone receptor from breast cancer cells (1999)
    Springer
    Molecular and cellular biochemistry 199 (1999), S. 49-56 
    Details
    ISSN: 1573-4919
    Keywords: progesterone receptor ; breast cancer ; steroid receptor agonists ; antagonists ; T47D cells ; RU486
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract T47D cells, cultured in medium containing serum stripped of endogenous steroids, proliferate in response to treatment with the progesterone receptor (PR) agonist, R5020 or the PR agonist/antagonist, RU486, whereas the full PR antagonist, ZK98299 has no proliferative effects. Under estrogenized conditions, all of the PR ligands tested inhibit cell growth [23]. In order to determine whether the levels or phosphorylation state of PR are reflected in the growth patterns of T47D cells, we monitored the effects of these PR ligands on the immunoblotted PR band intensities, the relative intensities, of PR-A and PR-B, and their phosphorylation states that are reflected in their altered mobility during SDS-PAGE. Under conditions where the PR ligands inhibit cell proliferation, each ligand had distinctively different qualitative and quantitative effects on PR. Short term treatment of the cells with R5020 or RU486 induced a characteristic phosphorylation-dependent upshift of both PR-A and PR-B. The phosphorylated PR was stable for up to 4 days after treatment of the cells with RU486, but was down regulated between 6-24 h after treatment with R5020. No replenishment of PR in cells treated with R5020 was detected. ZK98299, at concentrations tested, had no qualitative or quantitative effects on PR. Culturing cells for 8 days in medium containing steroid-depleted serum caused a significant reduction in the PR band intensity without causing a change in the ratio of PR-A and PR-B or their phosphorylation states. This decrease in the PR band intensity was reversed by maintaining the cells in 1 nM estrogen, but was potentiated by RU486 or ZK98299. These observations support the view that decreased PR levels may play a role in the stimulatory effects of R5020 and RU486 when cells are cultured under non-estrogenized conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006982528297
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  • 35
    Electronic Resource
    Electronic Resource
    The Metabolism of Atypical Antipsychotic Drugs: An Update (1999)
    Springer
    Annals of clinical psychiatry 11 (1999), S. 145-158 
    Details
    ISSN: 1573-3238
    Keywords: clozapine ; olanzapine ; quetiapine ; risperidone ; sertindole ; ziprasidone ; metabolism ; pharmacokinetics ; flavin-containing monooxygenases ; glucuronidation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This paper reviews the current literature describing the metabolism of both multi-receptor clozapine analogue atypical antipsychotic drugs (clozapine, olanzapine, and quetiapine) and serotonin-dopamine antagonist atypical antipsychotic drugs (risperidone, sertindole and ziprasidone), to highlight the significance of those data in the context of clinical practice. The former group of atypical antipsychotic drugs shares a similar tricyclic structural nucleus and are metabolized through three major categorical metabolic pathways—N +-oxidation, N-glucuronidation, and phases 1 and 2 biotransformation with final glucuronidation before renal excretion. Differing in clozapine and olanzapine, quetiapine has incomplete data describing its metabolism. The latter group of atypical antipsychotic drugs has diversified chemical structures and absence of data on N +-oxidation and N-glucuronidation in the literature. But their metabolic routes in phase 1 biotransformation are versatile although current data are far from completion. No apparent significant drug interactions in clinical practice are reported, although QT prolongation is implicated in all those three drugs. None of all six atypical antipsychotic drugs are identified as significant inhibitors or inducers to any co-administered medication. The author suggests the need for more research to address some pertinent clinical issues in the metabolism of those drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022312111429
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  • 36
    Electronic Resource
    Electronic Resource
    Effects of antiprogestins on the rate of proliferation of breast cancer cells (1999)
    Springer
    Molecular and cellular biochemistry 198 (1999), S. 141-149 
    Details
    ISSN: 1573-4919
    Keywords: T47D cells ; breast cancer ; cellular proliferation ; progesterone ; estradiol ; steroid receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract We have examined the influence of progestins (progesterone, R5020) and antiprogestins (RU486, ZK98299, Org 31710 and Org 31806) on the rate of proliferation of wild type T47D cells cultured in whole fetal bovine serum (FBS) or in single charcoal stripped fetal bovine serum (SSFBS). All of the progesterone antagonists RU486, ZK98299 and two novel antiprogestins Org 31710 and Org 31806 inhibited cell proliferation when cells were cultured in FBS. In contrast, all of the antiprogestins with the exception of ZK98299 enhanced cell growth when cells were cultured in SSFBS. This stimulatory effect of RU486 was observed only at a high concentration of the ligand (1 μM). The effect of R5020, however, was concentration independent. The number of cells in the presence of RU486 was ~ 600% followed by R5020 ~ 400% above control values after a 28 day culturing period. In contrast, when the cells were grown in the presence of medium containing non-stripped whole serum, RU486 inhibited the extent of cell proliferation by 45%. Estradiol (E2) stimulated the rate of proliferation in cells cultured in SSFBS. Similar to when cells were cultured in whole serum, the antiprogestins inhibited cell growth in E2-supplemented SSFBS. Detection of the growth enhancement effects of progesterone receptor (PR) ligands such as RU486 and R5020 on the cells grown in charcoal-stripped medium appear to require the removal of E2 by charcoal stripping of the serum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006945813508
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  • 37
    Electronic Resource
    Electronic Resource
    A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug (1999)
    Springer
    Investigational new drugs 17 (1999), S. 49-56 
    Details
    ISSN: 1573-0646
    Keywords: pharmacokinetics ; capecitabine ; 5-fluorouracil ; phase I trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 μ Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5′-DFCR, 5′-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006263400888
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  • 38
    Electronic Resource
    Electronic Resource
    A Sensitive Docetaxel Assay in Plasma by Solid-Phase Extraction and High Performance Liquid Chromatography – UV Detection: Validation and Suitability in Phase I Clinical Trial Pharmacokinetics (1999)
    Springer
    Investigational new drugs 17 (1999), S. 325-333 
    Details
    ISSN: 1573-0646
    Keywords: docetaxel ; plasma assay ; clinical trials ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have developed a specific and sensitive method aiming atdocetaxel (Taxotere®) determination in plasma of treatedpatients. This involved solid-phase extraction of 1 ml of plasmaonto carboxylic acid (CBA) grafted silica cartridges followed byreversed-phase liquid chromatography with UV detection. The bestselectivity was obtained through the use of C18 Uptisphere® asstationary phase. The low limit of quantitation obtained (LOQ:5 ng/ml) allowed measurements of docetaxel up to 24 hours afterone-hour infusions with low dosages of drug (60 mg/m2). Themethod was applied successfully to monitor docetaxel plasma levelswithin two protocols associating fixed dosages of either methotrexate or gemcitabine with escalating doses of Taxotere®.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006327302041
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  • 39
    Electronic Resource
    Electronic Resource
    Toward Checkmate: Biology and Breast Cancer Therapy for the New Millennium (1999)
    Springer
    Investigational new drugs 17 (1999), S. 417-427 
    Details
    ISSN: 1573-0646
    Keywords: breast cancer ; growth factors ; metalloproteinase ; angiogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A better understanding of the biology of breast cancer should leadto the rational development of new treatments and the ability tocustomize therapy for individual patients. Though promising intheory, translating advances in biological knowledge to the clinichas been difficult. Recently several areas of research haveproduced treatments which have entered clinical trials; three willbe reviewed here. The growth of breast cancer is regulated bygrowth factors and their receptors; amplification or overexpressionis associated with poor prognosis. As such inhibition of growthfactors and/or growth factor receptors may provide an idealtherapeutic target. Herceptin binds to c-erbB-2, a member of theepidermal growth factor receptor family. Significant responses wereseen in patients with c-erbB-2 overexpressing breast cancer withHerceptin administered as a single agent or in combination withchemotherapy. Herceptin was approved by the Food and DrugAdministration in late 1998. Breast cancer invasion and metastasisrequires degradation of the surrounding basement membrane by matrixmetalloproteinases and other proteolytic enzymes. Syntheticinhibitors of these enzymes are now in clinical trials. Breastcancers must stimulate angiogenesis, the growth of new bloodvessels, in order to grow beyond a few millimeters in diameter.This nascent vascular network provides another opportunity fortherapy. Preclinical models support the critical role ofangiogenesis and the therapeutic benefit of angiogenesisinhibition; clinical trials are underway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006311227965
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  • 40
    Electronic Resource
    Electronic Resource
    Evaluation of seprase activity (1999)
    Springer
    Clinical & experimental metastasis 17 (1999), S. 67-72 
    Details
    ISSN: 1573-7276
    Keywords: breast cancer ; extracellular matrix ; gelatinase ; invasion ; matrix metalloproteinase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Seprase is a serine protease that is integral to the plasma membrane and is overexpressed by invasive tumor cells (Piñeiro-Sánchez et al., J Biol Chem 1997; 272: 7595–601; Monsky et al., Cancer Res 1994; 54: 5702–10). Seprase activity is most often assessed by zymography, which is not a quantitative assay. This study establishes a relatively simple and quantitative method for determining seprase activity. The degradation of a 3H-gelatin substrate is measured in the presence of 5 mM EDTA which inhibits matrix metalloproteinases but not seprase. The quantitative character of the assay was demonstrated using partially purified seprase from chicken embryos, a preparation that lacks detectable matrix metalloproteinase activity. In this assay, release of 3H-gelatin fragments is linear over time for 1.5 μg/assay seprase concentration as well as for preparations concentrated or diluted by five fold (7.5 μg/assay and 0.3 μg/assay respectively). Additional experiments were performed to validate the quantification of seprase activity using the radiographic assay by comparing the results to zymography. Exposure to 22 or 37 °C results in maximal seprase activity while exposure to 80 or 100 °C completely abolishes seprase activity in both zymography and the radiographic assay. Exposure to 60 °C abolished seprase activity as judged by zymography, but about 50% gelatinase activity was observed using the 3H-gelatin substrate. Immunopreciptiation with seprase-specific antibody specifically removed seprase and lowered the seprase activity remaining in the extracts as judged by both assays. Investigation of the seprase that was partially purified from human breast cancer tissue revealed that its specific activity (cpm gelatin fragments released/ {mg protein×h}) is five times greater than that of seprase purified from chicken embryos. This assay will be useful for determining the seprase activity in extracts of tumor tissues and cells as well as for identifying inhibitors of seprase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026430206274
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  • 41
    Electronic Resource
    Electronic Resource
    ACNU, MTX And 5-FU Penetration of Rat Brain Tissue and Tumors (1999)
    Springer
    Journal of neuro-oncology 45 (1999), S. 9-17 
    Details
    ISSN: 1573-7373
    Keywords: ACNU ; MTX ; 5-FU ; pharmacokinetics ; leptomeningeal tumor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The distribution of radio-labeled ACNU, MTX and 5-FU in brain and tumor tissue was studied in female Wistar rats by macroautoradiography after intrathecal administration. In normal rats, ACNU and 5-FU, administered intracisternally, distributed rapidly in the subarachnoid space, ventricular system and cerebrospinal fluid (CSF). 5-FU and MTX penetrated the brain deeply; the diffusional transport of ACNU was limited to a depth of 1 or 2 mm from the CSF surface of the brain. MTX and 5-FU clearance into the blood circulation was rather slow while ACNU cleared relatively quickly. The half time of ACNU, 5-FU and MTX radioactivity at the ventricular surface was 10, 21, and 110 min, respectively, at their maximal concentration after intracisternal administration. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 cells, the distribution patterns of ACNU, 5-FU, and MTX were essentially the same as in normal rats despite 10–20 cell layers of tumor growing in the subarachnoid space. 5-FU and MTX were able to penetrate tumor masses in the subarachnoid space; MTX penetration was slower than that of 5-FU and ACNU failed to penetrate to more than a depth of 1 or 2 mm from the tumor surface.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006377312403
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  • 42
    Electronic Resource
    Electronic Resource
    Application of a Combined “Effect Compartment/Indirect Response Model” to the Central Nervous System Effects of Tiagabine in the Rat (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 301-323 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; effect compartment model ; indirect response ; sigmoid E max ; tiagabine ; GABA uptake inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (β), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg −1 $$(\bar x \pm SE,{\text{ }}n = 23)$$ $$96 \pm 9$$ ml min -1 kg−1, 1.5ŷ0.1 L kg−1 and 20ŷ0.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo=0.030 min −1 and kout=81 min−1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates $$(\bar x \pm SE)$$ were E0=155 ŷ 6 μV, Emax=100 ŷ 5 μV, EC50=287 ŷ 7 ng ml−1, Hill factor=1.8 ŷ 0.2 and keo=0.030 ŷ 0.002 min −1. The results of this analysis show that for tiagabine the combined “effect compartment-indirect response” model can be simplified to the classical “effect compartment” model.
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    URL: http://dx.doi.org/10.1023/A:1020999114109
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  • 43
    Electronic Resource
    Electronic Resource
    Assuming Peripheral Elimination: Its Impact on the Estimation of Pharmacokinetic Parameters of Muscle Relaxants (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
    Details
    ISSN: 1573-8744
    Keywords: muscle relaxants ; peripheral elimination ; pharmacokinetics ; peripheral concentrations ; volume of distribution ; pharmacokinetic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10 ) and peripheral compartments(k20 ). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss ) are also mostly significant when k20 is smaller than k10 . Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20 , the rate of transfer from the central compartment (k12 ) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023286329945
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  • 44
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Dosage Regimen of Enrofloxacin in Buffalo Bulls after Intramuscular Administration (1999)
    Springer
    Veterinary research communications 23 (1999), S. 501-505 
    Details
    ISSN: 1573-7446
    Keywords: antibiotics ; buffalo ; disposition ; dosage ; enrofloxacin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The disposition kinetics and dosage regimen of enrofloxacin were investigated in breeding buffalo bulls following a single intramuscular administration of 5 mg/kg. The absorption half-life, half-life of the terminal phase, apparent volume of distribution and total body clearance were 0.262±0.099 h, 1.97±0.23 h, 0.61±0.13 L/kg and 210.2±18.6 ml/(kg.h), respectively. Therapeutic plasma levels (≥1 μg/ml) were maintained for up to 6 h. A satisfactory intramuscular dosage regimen for enrofloxacin in buffalo bulls would be 8.5 mg/kg followed by 8.0 mg/kg at 8 h intervals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006366507016
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  • 45
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Amoxicillin Trihydrate in Desert Sheep and Nubian Goats (1999)
    Springer
    Veterinary research communications 23 (1999), S. 507-514 
    Details
    ISSN: 1573-7446
    Keywords: amoxicillin ; bioavailability ; breed ; goats ; pharmacokinetics ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of amoxicillin were studied in five Desert sheep and five Nubian goats after intravenous (i.v.) or intramuscular (i.m.) administration of a single dose of 10 mg/kg body weight. Following i.v. injection, the plasma concentration-versus-time data were best described by a two-compartment open model. The kinetic variables were similar in both species except for the volume of the central compartment (Vc), which was larger in sheep (p〈0.05). Following i.m. injection, except for the longer half-life time of absorption in goats (p〈0.05), there were no significant differences in other pharmacokinetic parameters between sheep and goats. The route of amoxicillin administration had no significant effect on the terminal elimination half-life in either species. The bioavailability of the drug (F) after i.m. administration was high (〉0.90) in both species. These results indicate that the pharmacokinetics of amoxicillin did not differ between sheep and goats; furthermore, because of the high availability and short half-life of absorption, the i.m. route gives similar results to the i.v. route. Therefore, identical intramuscular and intravenous dose regimens should be applicable to both species.
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    URL: http://dx.doi.org/10.1023/A:1006318623854
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  • 46
    Electronic Resource
    Electronic Resource
    Comparative Anthelmintic Activity of Strategic Sustained Low-level Administration of Albendazole in Feed Pellets Compared to Single Doses of Closantel and Tetramisole against Natural Ovine Parasitic Gastroenteritis (1999)
    Springer
    Tropical animal health and production 31 (1999), S. 193-204 
    Details
    ISSN: 1573-7438
    Keywords: albendazole ; anthelmintic ; closantel ; control ; delivery ; dosage ; Haemonchus contortus ; in-feed ; pharmacokinetics ; sheep ; tetramisole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The strategic use of single therapeutic doses of closantel, tetramisole or sustained low-level administration of albendazole in feed pellets in controlling naturally acquired parasitic gastroenteritis in sheep was investigated on a farm in semi-arid Rajasthan, India. A total of 303 5- to 6-month-old sheep were divided into three groups. Two groups were dosed with single therapeutic doses of closantel and tetramisole and the third group was given a low-level medication with albendazole through feed pellets for 30 days. Faecal egg counts revealed significantly lower counts (p〈0.001) in the group treated with closantel compared to the other two groups. The faecal egg counts in the group receiving sustained low-level albendazole rose after withdrawal of the medication but remained significantly lower than those in the group treated with tetramisole up to 7 weeks after treatment (p〈0.05). On the other hand, in the group treated with tetramisole, the mean faecal egg count rose from 3 weeks after treatment and remained continuously higher than those in any other group up to 12 weeks after treatment. The closantel-treated group gained more body weight but the first six-monthly greasy fleece yield was greater in the group treated with medicated pellets. During the first 3 months of the experiment, three animals in the group treated with tetramisole died of parasitic gastroenteritis. Following sustained low-level administration of albendazole in feed pellets, the plasma disposition curve of both the sulphoxide and sulphone metabolites reached its plateau level by day 5 and remained almost constant thereafter. The comparative cost-effectiveness of the three treatment regimes during the first 3 months of treatment was best for the group treated with closantel followed by the group treated with medicated feed pellets.
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    URL: http://dx.doi.org/10.1023/A:1005223025851
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  • 47
    Electronic Resource
    Electronic Resource
    Some Pharmacokinetic Parameters of Eprinomectin in Goats following Pour-on Administration (1999)
    Springer
    Veterinary research communications 23 (1999), S. 449-455 
    Details
    ISSN: 1573-7446
    Keywords: eprinomectin ; goat ; pharmacokinetics ; topical application
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Some pharmacokinetic parameters of eprinomectin were determined in goats following topical application at a dose rate of 0.5 mg/kg. The plasma concentration versus time data for the drug were analysed using a one-compartment model. The maximum plasma concentration of 5.60±1.01 ng/ml occurred 2.55 days after administration. The area under the concentration–time curve (AUC) was 72.31±11.15 ng day/ml and the mean residence time (MRT) was 9.42±0.43 days. Thus, the systemic availability of eprinomectin to goats was significantly lower than that for cows. The low concentration of eprinomectin in the plasma of goats suggests that the pour-on dose of 0.5 mg/kg would be less effective in this species than in cows. Further relevant information about the optimal dosage and residues in the milk of dairy goats is needed before eprinomectin should be used in this species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006373609314
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  • 48
    Electronic Resource
    Electronic Resource
    Lack of Sex-influence on the In Vitro Metabolism of Ivermectin by Hepatic Microsomal Preparations from Cattle (1999)
    Springer
    Veterinary research communications 23 (1999), S. 223-227 
    Details
    ISSN: 1573-7446
    Keywords: cattle ; gender ; ivermectin ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006249009553
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  • 49
    Electronic Resource
    Electronic Resource
    Influence of Diet Type and Pretreatment Fasting on the Disposition Kinetics of Albendazole in Sheep (1999)
    Springer
    Veterinary research communications 23 (1999), S. 229-240 
    Details
    ISSN: 1573-7446
    Keywords: albendazole ; diet ; fasting ; green fodder ; pharmacokinetics ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of the quality and quantity of diets on the disposition kinetics of albendazole were studied in sheep in two different experiments. The plasma concentration profiles of albendazole sulphoxide and albendazole sulphone were measured following intraruminal administration of albendazole at 5.0 mg/kg body weight in weaner sheep offered three different diets: 100% green Sorghum spp., 100% dry mature Cenchrus ciliaris hay and a 50:50 mix of these two diets. The peak plasma concentrations and the availability of the albendazole metabolites, as measured by the area under the concentration–time curve, were significantly higher (p〈0.01) in the animals offered exclusively dry fodder compared to other diets. Changing the diet from dry to green fodder resulted in a significantly lower systemic availability of the drug metabolites. It is suggested that a decreased transit time of the digesta in the bowel on the green diet, with its high water content, limited the systemic availability of the drug by reducing the time available for gastrointestinal absorption. An experiment on the influence of different levels of pretreatment fasting on the pharmacokinetics of albendazole revealed significantly higher (p〈0.05) plasma concentrations of the anthelmintically active sulphoxide metabolite from 12 h onwards following administration of the drug in animals subjected to 24 h of pretreatment fasting compared to other groups with pretreatment fasting of 8, 12 or 18 h. The area under the concentration–time curve and the minimum residence time of the drug metabolites were significantly greater (p〈0.05) in animals that had been fasted for 24 h. It is suggested that fasting induces a decrease in the flow of digesta through the gastrointestinal tract of ruminants and prolongs the duration of dissolution of the drug, resulting in enhancement of the absorption of albendazole and of the systemic availability of its metabolites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006201226391
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  • 50
    Electronic Resource
    Electronic Resource
    Rapid Attainment of Steady-State Plasma Drug Concentrations Within Precise Limits in Multicompartment Mammillary Systems (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 325-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have previously described a method of rapidly obtaining a specified steady-state plasma concentration of an intravenous drug within precise limits. However the method is limited to drugs whose disposition may be characterized by an open two-compartment system. In this paper, we illustrate how the method can be extended to drugs whose disposition may be characterized by a mammillary model with any number of compartments. Refinements of our previous technique are also described.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020951230947
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  • 51
    Electronic Resource
    Electronic Resource
    Population Pharmacokinetics and Pharmacodynamics of the Anti-CD11a Antibody hu1124 in Human Subjects with Psoriasis (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 397-420 
    Details
    ISSN: 1573-8744
    Keywords: psoriasis ; hu1124 ; CD11a ; CD3-positive lymphocytes ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1–3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration–time profile suggested that the clearance of hu1124 was saturable above 10 μg/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (〉0.025 μg/ml) in the plasma. When hu1124 levels fell below 3 μg/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7–10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 μg/ml and saturation required more than 10 μg/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 μg/ml, thereby reducing the clearance rate of hu1124 with increasing dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020917122093
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  • 52
    Electronic Resource
    Electronic Resource
    Drug–Drug Pharmacodynamic Interaction Detection by a Nonparametric Population Approach. Influence of Design and of Interindividual Variability (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 531-554 
    Details
    ISSN: 1573-8744
    Keywords: drug–drug interactions ; NPML ; experimental design ; pharmacodynamic variability ; pharmacokinetics ; entropy ; covariate ; second stage model ; controlled trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Population approaches are appealing methods for detecting then assessing drug–drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug–drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023290530853
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  • 53
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Hemostatic Effects of Saruplase in Patients with Acute Myocardial Infarction: Comparison of Infusion, Single-Bolus, and Split-Bolus Administration (1999)
    Springer
    Journal of thrombosis and thrombolysis 8 (1999), S. 213-221 
    Details
    ISSN: 1573-742X
    Keywords: saruplase ; pharmacokinetics ; bolus administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Saruplase, or unglycosylated, single-chain urokinase-type plasminogen activator (scu-PA) selectively activates fibrin-bound plasminogen, and is subsequently converted to its two-chain derivative tcu-PA (urokinase) by plasmin. The efficacy of a 20 mg IV bolus followed by an infusion of 60 mg over 1 hour (standard regimen) has been demonstrated in acute myocardial infarction (AMI). The Bolus Administration of Saruplase in Europe (BASE) study compared the efficacy of standard therapy, single bolus (80 mg), and split bolus (2 × 40 mg at 30-minute intervals) in AMI. In a substudy of BASE, the pharmacokinetics of total u-PA activity (amidolytic activity after plasmin treatment), high molecular weight (HMW) u-PA antigen, and tcu-PA activity were compared in patients receiving standard therapy (n = 4), single bolus (n = 4), or split bolus (n = 5). Total u-PA activity and HMW u-PA antigen were similar. The maximum concentration (Cmax,, mean ± SD) of total u-PA activity was 2.2 ± 0.3 µg/mL after standard therapy, 16.3 ± 3.9 µg/mL after single bolus, and 8.2 ± 1.6 ug/mL after split bolus. The area under the concentration versus time curve (AUC) values of total u-PA activity were 1.7 ± 0.1 µg/mL*h (standard therapy), 4.0 ± 0.9 µg/mL*h (bolus), and 3.0 ± 0.7 µg/mL*h (split bolus). The dominant initial half-lives (t1/2 α) were 7.1 ± 1.1 minutes (standard), 8.8 ± 0.8 minutes (bolus), and 5.1 ± 2.1 minutes (split bolus). Maximum plasma concentrations of of tcu-PA activity were observed at 5.2 ± 7 minutes (standard), 21 ± 10 minutes (bolus), and 42 ± 2 minutes (split bolus). Cmax was lowest after standard therapy (0.6 ± 0.3 µg/mL), highest after bolus (4.2 ± 2.2 µg/mL), and approximately twice as high as standard therapy after split bolus (1.3 ± 0.8 µg/mL). After standard therapy the mean fibrinogen concentration decreased gradually from approximately 300 mg/dL to 70 mg/dL at 90 and 120 minutes. After a single bolus the fibrinogen concentration decreased below the limit of quantification within 30 minutes and remained there for at least 120 minutes. Directly after the second 40 mg dose of the split bolus, the fibrinogen levels had an accelerated and more pronounced decrease to approximately 65 mg/dL at 90 and 120 minutes. A single bolus results in very high early total u-PA activity, which accelerates the appearance of tcu-PA activity and fibrinogen consumption. The pharmacokinetics and hemostatic effects of the split-bolus regimen are more comparable with those of standard therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008914321384
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  • 54
    Electronic Resource
    Electronic Resource
    A Compartmental Analysis of the Pharmacokinetics of Propofol in Sheep (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 329-338 
    Details
    ISSN: 1573-8744
    Keywords: propofol ; anaesthesia ; pharmacokinetics ; compartment models ; effect compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020903315017
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  • 55
    Electronic Resource
    Electronic Resource
    Indirect-Response Modeling of Desmopressin at Different Levels of Hydration (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 513-529 
    Details
    ISSN: 1573-8744
    Keywords: desmopressin ; indirect-response modeling ; overhydration ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20ml·kg −1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 μg of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 β) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc ) and at steady state (Vss ) were estimated to be 1.34 (SD 0.35) ml·min −1 ·kg −1 , 151 (SD28) ml·kg −1 , and 386 (SD 63) ml·kg −1 , respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0 ). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p〈0.0001). The mean values for IC50 and the sigmoidicity factor (γ) were 3.7 (SD 1.2) pg·ml −1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023238514015
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  • 56
    Electronic Resource
    Electronic Resource
    Constructing a Prediction Interval for Time to Reach a Threshold Concentration Based on a Population Pharmacokinetic Analysis: An Application to Basiliximab in Renal Transplantation (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 213-230 
    Details
    ISSN: 1573-8744
    Keywords: prediction interval ; pharmacokinetics ; population analysis ; NONMEM ; inverse regression ; immunosuppressives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor α-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 μg/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7–52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7–58.3 days.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020658023774
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  • 57
    Electronic Resource
    Electronic Resource
    Modeling Interactions between Adrenal Suppression and T-Helper Lymphocyte Trafficking during Multiple Dosing of Methylprednisolone (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 559-575 
    Details
    ISSN: 1573-8744
    Keywords: T-helper cells ; trafficking ; rebound ; corticosteroids ; circadian rhythm ; methylprednisolone ; drug interactions ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.
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    URL: http://dx.doi.org/10.1023/A:1020974408657
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  • 58
    Electronic Resource
    Electronic Resource
    Relationship Between Etomidate Plasma Concentration and EEG Effect in the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 924-929 
    Details
    ISSN: 1573-904X
    Keywords: etomidate ; pharmacokinetics ; pharmacodynamics ; rat ; electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter. Methods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n = 6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5−7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia. Results. A mean dose of 8.58 ± 0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93 ± 6 ml/min/kg, 4.03 ± 0.24 l/kg and 59.4 ± 10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65 ± 0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44 ± 0.03 μg/ml. Conclusions. The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5−7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018894523734
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  • 59
    Electronic Resource
    Electronic Resource
    Prediction of Pharmacokinetic Parameters and the Assessment of Their Variability in Bioequivalence Studies by Artificial Neural Networks (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 944-948 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; neural networks ; prediction ; pharmacokinetics ; verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, cmax, tmax) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for cmax, and the presence of food, blood pressure, and body-frame for tmax. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018857108713
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  • 60
    Electronic Resource
    Electronic Resource
    A Physiological Pharmacokinetic Model for Solute Disposition in Tissues Below a Topical Application Site (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1392-1398 
    Details
    ISSN: 1573-904X
    Keywords: topical application ; dermal absorption ; cutaneous perfusion ; pharmacokinetics ; binding ; half life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. Methods. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. Results. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. Conclusions. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018998908655
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  • 61
    Electronic Resource
    Electronic Resource
    Venous Irritation, Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 930-938 
    Details
    ISSN: 1573-904X
    Keywords: submicron lipid emulsion ; supersaturation ; tirilazad ; venous irritation ; pharmacokinetics ; tissue distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p 〉 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower Vss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p 〈 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018846607804
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  • 62
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    Distribution and Binding Kinetics of Ciprofloxacin and Ofloxacin in the Hindlimb of the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 587-591 
    Details
    ISSN: 1573-904X
    Keywords: quinolones ; pharmacokinetics ; permeability ; tissue binding ; hindlimb
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011939616948
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  • 63
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    Pharmacokinetics of Methotrexate in the Extracellular Fluid of Brain C6-Glioma After Intravenous Infusion in Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1219-1225 
    Details
    ISSN: 1573-904X
    Keywords: C6-glioma ; methotrexate ; microdialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats. Methods. Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay. Results. Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 ± 5.3%. MTX concentrations in tumor ECF represented about 1−2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2α, t1/2β, MRT, fb, Vd, and CLT), except for a 1.7-fold increase of AUCPlasma and a 3.8-fold increase in AUCECF which resulted in a 2.3-fold increase in penetration (AUCECF/AUCPlasma). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters. Conclusions. High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018945529611
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  • 64
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    Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1226-1232 
    Details
    ISSN: 1573-904X
    Keywords: HI-240 ; nonnucleoside inhibitor ; pharmacokinetics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values. Results. HI-240 had an elimination half-life of 78.3 ± 2.0 min after i.v. administration and 196.8 ± 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 ± 61 ml/h/kg after i.v. administration and 9339 ± 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t1/2ka and a tmax values of less than 10 min. Following oral administration, HI-240 was absorbed with a t1/2ka of 4.2 ±1.1 min and a tmax of 95.1 ± 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%. Conclusions. The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1014814313681
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  • 65
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    Pharmacokinetic Features and Metabolism of Calphostin C, A Naturally Occurring Perylenequinone with Antileukemic Activity (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1003-1009 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; Calphostin C ; HPLC ; perylenequinone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. Methods. HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. Results. An intracellular exposure level (AUC0−6h) of 257 μM·h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 μM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 μM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated tmax was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a tmax of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018923430094
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  • 66
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    Improved Lipid Lowering Activity of Bezafibrate Following Continuous Gastrointestinal Administration: Pharmacodynamic Rationale for Sustained Release Preparation of the Drug (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1093-1097 
    Details
    ISSN: 1573-904X
    Keywords: bezafibrate ; hyperlipidemia ; pharmacodynamics ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018900219616
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  • 67
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    Electronic Resource
    Dopamine release in the prefrontal cortex in response to memantine following sub-chronic NMDA receptor blockade with memantine: a microdialysis study in rats (1999)
    Springer
    Journal of neural transmission 106 (1999), S. 803-818 
    Details
    ISSN: 1435-1463
    Keywords: Keywords: Dopamine ; memantine ; microdialysis ; pharmacokinetics ; pre-frontal cortex.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist which blocks the NMDA receptor with moderate-affinity in a use- and voltage dependent manner. In clinical practice it is used chronically in the treatment of dementia and does not induce psychotomimetic effects as, high affinity, uncompetitive antagonists. Thus, it was of interest to determine dopamine (DA) and metabolite (DOPAC – dihydroxyphenylacetic acid and HVA – homovanillic acid) concentrations in the prefrontal cortex (PFC) in response to 14 days administration of memantine (20 mg/kg/day). It was previously determined that in rats this treatment induces sensitization to the locomotor effect and tolerance to the learning impairing properties of high doses of memantine. Acute administration of memantine (20 mg/kg, ip) did not affect dopamine levels in the PFC. It did however increase DA metabolite (DOPAC and HVA) concentrations. Administration of memantine (20 mg/kg/day) for 14 days before the acute challenge only slightly changed memantine's effect on PFC neurochemistry even though pharmacokinetic tolerance was observed. When memantine was administered to the sham group, which had been repeatedly treated with Hypnorm (including neuroleptic), an increase in PFC dopamine and metabolite content was seen. In accordance with the fact that memantine does not possess psychotomimetic activity at therapeutically relevant doses, these experiments showed that it does not affect the prefrontal cortex dopamine levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007020050201
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  • 68
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    Electronic Resource
    Loss of heterozygosity in BRCA1 and BRCA2 markers and high‐grade malignancy in breast cancer (1999)
    Springer
    Breast cancer research and treatment 53 (1999), S. 9-17 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; microsatellites ; prognostic factors ; 17q21 region ; 13q12‐13 region
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Loss of heterozygosity (LOH) in loci of the 17q21 and 13q12‐13 regions can collaborate in the inactivation of BRCA1, BRCA2, and possibly other genes implicated in the pathogenesis of breast carcinomas. We investigate allelic losses in microsatellites of the BRCA1 and BRCA2 regions, and their correlations with seven pathologic parameters in 140 breast carcinomas. Those cases showing LOH in the region of the RB gene, 13q14, were excluded from the study. The LOH analysis was performed by amplifying DNA by PCR, using four markers of the 17q21 region (D17S856, D17S855, D17S1323, and D17S1327) and four markers of the 13q12‐13 region (D13S290, D13S260, D13S310, and D13S267). LOH in the BRCA1 region was found in 47% of tumors, correlating significantly with estrogen receptor content (p = 0.025), progesterone receptors (p = 0.004), higher grade (p = 0.0008), peritumoral vessel invasion (p = 0.001), and lymph node metastases (p = 0.002). When we excluded the cases with LOH in the BRCA2 region and those not informative for it, the significance disappeared. In the BRCA2 region, a rate of LOH of 51% was found; it correlated significantly with estrogen receptor content (p = 0.002), progesterone receptors (p =0.03), peritumoral vessel invasion (p = 0.005), higher grade (p =0.002), and lymph node metastases (p = 0.001). When cases with BRCA1 losses and those not informative were excluded, again the significance disappeared. Concomitant losses in the BRCA1 and BRCA2 regions were found in 32% of cases, correlating significantly with lymph node metastases (p = 0.0002), estrogen receptor content (p = 0.003), progesterone receptors (p = 0.001), histologic grade (p =0.01), and peritumoral vessel invasion (p = 0.0004). These results suggest that concomitant losses in both regions could have a functional effect, influencing the presence of a poor tumor pathophenotype in breast carcinomas.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006082117266
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  • 69
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    Quantitative changes in cytological molecular markers during primary medical treatment of breast cancer: A pilot study (1999)
    Springer
    Breast cancer research and treatment 53 (1999), S. 51-59 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; neoadjuvant therapy ; FNA ; estrogen receptor ; progesterone receptor ; p53 ; Bcl‐2 ; Ki67 ; SPF ; ploidy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aim: To quantify the changes in biological molecular markers during primary medical treatment in patients with operable breast cancer and to assess their possible relationship with response to treatment. Methods: The treatment group consisted of 31 patients with operable breast carcinomas, median age 57 years (range 41–67), treated with four 3‐weekly cycles of chemotherapy with Mitoxantrone, methotrexate (± mitomycin C), and tamoxifen before surgery. Fine needle aspiration (FNA) was used to obtain samples from patients prior to and at 10 or 21 days post‐treatment. The following molecular markers were assessed: estrogen receptor (ER), progesterone receptor (PgR), p53, Bcl‐2, and Ki67 measured by immunocytochemistry, and ploidy and S‐phase fraction (SPF) by flow cytometry. To evaluate the reproducibility of the technique, repeat FNA was performed in a separate non‐treatment control group of 20 patients and the same molecular markers assessed, two weeks after the first sample with no intervening treatment. Results: The non‐treatment control group showed a high reproducibility for the measurement of molecular markers from repeat FNA. In the treatment group there was a non‐significant reduction in SPF and a significant reduction (p = 0.005) in Ki67. Patients who responded to neoadjuvant therapy were more likely to have a reduction in these two markers than those who failed to respond. Similarly, a reduction in ER scores was observed between the first and second samples (p = 0.04). For PgR, the change between the first and second samples was not significant although there was a significant difference between responders and non‐responders (p = 0.03). All nine patients with an increase in PgR were responders. No significant changes in p53 or Bcl‐2 were observed during treatment. Conclusion: Molecular markers can be adequately measured from FNA samples prior to and during neoadjuvant therapy. Changes in cellular proliferation and hormone receptors have been shown that may be related to tumour response. These relationships should be assessed in a larger cohort of patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006179511178
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  • 70
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    Electronic Resource
    Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III). (1999)
    Springer
    Breast cancer research and treatment 53 (1999), S. 121-135 
    Details
    ISSN: 1573-7217
    Keywords: HPV 16 ; breast cancer ; CIN III ; PCR ; southern blot ; in situ hybridization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Women with both a history of high grade cervical intraepithelial neoplasia (CIN III) and breast carcinoma as second primary cancer were selected for studying the presence of HPV in breast carcinomas. Paraffin embedded material from 38 patients with 41 breast carcinoma cases after CIN III were examined by polymerase chain reaction (PCR) and in situ hybridization. By PCR we detected HPV 16 DNA in 19 out of 41 cases (46%) of the breast carcinomas. One case proved to be HPV 16 positive also by in situ hybridization. HPV 16 was also detected in 32 out of the 38 patients with CIN III (84%). All HPV 16 positive breast carcinomas were HPV 16 positive in their corresponding CIN III lesions. Eight patients with diagnosed breast cancer before the CIN III lesions were used as controls. None of these had HPV positive breast carcinomas. No cases were positive for HPV 11, 18, or 33. HPV 16 was detected in the primary tumours, in local metastases from HPV 16 positive tumours, in a distant HPV 16 positive breast carcinoma metastasis to the colon, and in other primary cancers in patients with HPV 16 positive breast carcinomas and HPV 16 positive CIN III. Estrogen and progesterone receptors were quantified in the HPV positive and HPV negative breast carcinomas, and there was no significant difference in the fraction positive in the two groups. Oncogenic HPV DNA might be transported from an original site of infection to other organs by blood or lymph, and possibly be a factor in the development of cancer in different organs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006162609420
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  • 71
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    Genetic anticipation and breast cancer: a prospective follow‐up study (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 21-28 
    Details
    ISSN: 1573-7217
    Keywords: age of diagnosis ; ascertainment ; breast cancer ; genetic anticipation ; prospective cohort family study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Genetic anticipation is characterized by an earlier age of disease onset, increased severity, and a greater proportion of affected individuals in succeeding generations. The discovery of trinucleotide repeat expansion (TRE) mutations as the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders has led to a resurgence of interest in this phenomenon. Because of the difficulties presented to traditional genetics by complex diseases, the testing for genetic anticipation coupled with TRE detection has been proposed as a strategy for expediting the identification of susceptibility genes for complex disorders. In the case of breast cancer, a number of previous studies found evidence consistent with genetic anticipation. It is known that a proportion of such families are linked to either BRCA1 or BRCA2, but no TRE mutations have been identified. It has been shown that the typical ascertainment employed in studies purporting to demonstrate genetic anticipation combined with unadjusted statistical analysis can dramatically elevate the type I error. We re‐examine the evidence for anticipation in breast cancer by applying a new statistical approach that appears to have validity in the analysis of anticipation to data ascertained from a recent follow‐up of a large prospective cohort family study of breast cancer. Using this approach, we find no statistically significant evidence for genetic anticipation in familial breast cancer. We discuss the limitations of our analysis, including the problem of adequate sample size for this new statistical test.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006151132592
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  • 72
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    Differential regulation of normal and tumoral breast epithelial cell growth by fibroblasts and 1,25‐dihydroxyvitamin D3 (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 29-39 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; cell interactions ; 1,25‐dihydroxyvitamin D3 ; fibroblast ; normal epithelial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Mesenchymal‐epithelial interactions are of paramount importance during normal and tumoral breast developments. We have investigated the paracrine growth regulation of normal and tumoral breast epithelial cells by fibroblasts derived from normal or pathological breast tissues. In some cases, breast cancer MCF‐7 cells or normal epithelial cells in primary culture were cocultured with fibroblasts in a Transwell system allowing diffusible factor exchanges. Alternatively, conditioned medium produced by fibroblast cultures was added to epithelial cell cultures. Fibroblasts were shown to stimulate the proliferation of normal and carcinoma cells through paracrine mechanisms. However, the paracrine exchanges appeared to be different in normal versus tumoral breast epithelial cell growth regulation. Moreover, vitamin D‐related compounds that have been proposed as anti‐tumoral drugs were studied for their ability to affect normal and tumoral mammary epithelial cell proliferation and to interfere with the growth‐regulatory activity of fibroblasts. Whereas vitamin D compounds inhibited MCF‐7 cell growth, they led to a marked stimulation of the proliferation of normal mammary epithelial cells. Moreover, it was shown that the vitamin D analog EB 1089 can block the mitogenic effect of fibroblast‐conditioned medium on tumoral but not normal breast epithelial cells. The differential effects of vitamin D compounds on cell proliferation provide further data in favor of the different behaviours of normal and tumoral mammary epithelial cells. The potential therapeutic use of vitamin D derivatives in the treatment of breast cancer is supported by these results but their growth‐stimulatory properties on normal epithelial cells cannot be overlooked.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006163418479
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  • 73
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    Electronic Resource
    Regulation of BAX and BCL‐2 expression in breast cancer cells by chemotherapy (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 107-117 
    Details
    ISSN: 1573-7217
    Keywords: apoptosis ; Bax ; Bcl‐2 ; breast cancer ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Optimizing chemotherapeutic drug delivery strategies relies, in part, on identification of the most clinically effective sequence, dose, and duration of drug exposure. The combination of dose intensive etoposide (VP‐16) followed by cyclophosphamide has clinical efficacy in the treatment of advanced breast cancer. However, molecular mechanisms that underlie the effectiveness of this combination of chemotherapeutic agents have not been investigated. In this study we investigated regulation of BAX and BCL‐2 expression by VP‐16 and cyclophosphamide as a potential mechanism for the induction of breast cancer cell death induced by this regimen. There was a dose and time dependent increase in BAX expression in the breast cancer cell lines MCF‐7, MDA‐MB‐435S, and MDA‐MB‐A231 following in vitro treatment with 50–100 μM VP‐16. Elevation of BAX protein expression in the presence of VP‐16 alone did not correlate with reduced viability or induction of apoptosis in MCF‐7, MDA‐MB‐435S, or MDA‐MB‐A231. VP‐16 did effectively block the breast cancer cell lines evaluated (MCF‐7 and MDA‐MB‐435S) at G2/M phase of the cell cycle, confirming activity of the drug in vitro. MCF‐7 and MDA‐MB‐435S cells that were pre‐treated with VP‐16 and subsequently exposed to 1.0–12.0 μg/m1 4‐hydroperoxycyclophosphamide (4HC), an active metabolite of cyclophosphamide, had markedly reduced viability when compared to matched controls treated with either VP‐16 or 4HC individually. Consistent with this loss of viability, exposure of all three cell lines to the combination of VP‐16 and 4HC resulted in higher BAX protein levels than those observed following treatment with either single agent. This combination of chemotherapeutic agents also resulted in reduced BCL‐2 expression. These observations suggest that combination chemotherapy may derive its efficacy, in part, through coordinated regulation of specific gene products associated with apoptosis. Characterization of molecular events that underlie susceptibility of specific tumor cells to combination chemotherapeutic regimens may lead to additional improvements in treatment strategies for this disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006175811676
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  • 74
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    Cathepsin D expression by cancer and stromal cells in breast cancer: an immunohistochemical study of 1348 cases (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 135-145 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; cathepsin D ; immunohistochemistry ; protease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study was aimed at investigating the influence of cathepsin D (CD) expression by cancer cells and stromal cells on breast cancer prognosis. This is a study of 1348 node‐positive (NPBC) and node‐negative (NNBC) breast cancers diagnosed between 1980 and 1986 and with a minimum follow‐up of 5.2 years. CD expression was assessed by immunohistochemistry on archival material using a polyclonal antibody. The expression by cancer and stromal cells was assessed separately and correlated with distant metastasis free (DMFS) and overall survival (OS). Cancer cells expressed CD (more than 10% cells expressing CD) in 38.9% of cases and reactive stromal cells in 43.6%. CD expression by reactive stromal cells, and not cancer cells, correlated with several factors of poor prognosis by cancer cells. A strong association was also found with expression of other proteases (stromelysin‐3, gelatinase A, and urokinase Plasminogen Activator) by these same reactive stromal cells. CD expression by cancer cells did not predict DMFS or OS but, by univariate analysis, CD expression by reactive stromal cells was associated with earlier recurrence and shorter survival in NNBC (p = 0.0425) and NPBC patients submitted to adjuvant chemotherapy (p = 0.0234). However, CD expression by reactive stromal cells remained a significant predictor of recurrence by multivariate analyses only in a subgroup of NPBC submitted to adjuvant chemotherapy. Overall, those data support the concept that proteases produced by reactive stromal cells are under cancer cell stimulation and that CD by stromal cells, and not cancer cells, influences the prognosis, but only in a subgroup of patients with breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006140213493
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  • 75
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    Assessment of quality of life in women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom subscale for the FACT‐B (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 187-197 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; endocrine therapy ; FACT‐B ; FACT‐ES ; quality of life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Existing quality of life instruments do not include adequate items to measure the side effects and putative benefits of hormonal treatments given in breast cancer. We report the development and validation of an 18 item endocrine subscale (ES) to accompany a standardised breast cancer quality of life measure, the Functional Assessment of Cancer Therapy (FACT‐B) [1]. The FACT‐ES (FACT‐B plus ES) was tested initially on 268 women with breast cancer receiving endocrine treatments. Alpha coefficients for all subscales demonstrated good internal consistency (range α = 0.65–0.87). Test‐retest reliability of the ES indicated good stability (r = 0.93, p 〈 0.001). Advanced breast cancer patients' quality of life was high, showing the efficacy of endocrine therapy, but women with primary disease reported better physical, social, and functional well‐being and fewer breast cancer concerns. Most frequently reported symptoms were loss of sexual interest (31%), weight gain (25%), and hot flushes (24%). Significant differences were found between treatment groups for hot flushes and vaginal dryness. Two assessments of the instrument's responsiveness to change were made; 32 women in a clinical trial of endocrine therapy and 18 women without breast cancer taking HRT completed the FACT‐ES at baseline, 4, 8, and 12 weeks. Trial patients reported significantly more symptoms at 8 and 12 weeks than at baseline. Women taking HRT reported significantly fewer or less severe symptoms than at baseline. In conclusion the FACT‐ES has acceptable validity and reliability and is sensitive to clinically significant change, making it suitable for clinical trials of endocrine therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006263818115
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  • 76
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    Induction of insulin‐like growth factor binding protein expression by ICI 182,780 in a tamoxifen‐resistant human breast cancer cell line (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 231-242 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; ICI 182 ; 780 ; IGFBPs ; tamoxifen resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Earlier studies in our laboratory demonstrated that the steroidal antiestrogen ICI 182,780 is very effective in abolishing the tamoxifen‐resistant proliferation of MCF 7/5‐23 cells [1]. In addition, preliminary binding studies showed that ICI 182,780 increased the binding of insulin‐like growth factor (IGF)‐I to the MCF 7/5‐23 cells, although this finding was not the result of an increase in the expression of the insulin‐like growth factor‐I receptor (IGF‐IR). Hence, we reasoned that the inhibition of tamoxifen‐resistant cell growth by ICI 182,780 might have been due to increased expression of insulin‐like growth factor binding proteins (IGFBPs). We observed the up‐regulation of non‐insulin‐suppressible IGF‐I binding in both the tamoxifen‐sensitive MCF 7/5‐21 cell line (1.5‐fold) and the tamoxifen‐resistant MCF 7/5‐23 cell line (2.5‐fold) after 5 days of treatment with ICI 182,780 (10−7 M) in serum‐free medium, suggesting a role for cell‐associated IGFBPs. Affinity cross‐linking experiments confirmed the presence of an IGF‐I:IGFBP complex of approximately 38‐kDa in tamoxifen or ICI 182,780‐treated cells. Western ligand blots showed higher levels of a soluble 30‐kDa IGFBP in media conditioned by either of the subclones that had been treated with ICI 182,780, an effect consistently opposed by estrogen (E2:10−9 M). RT‐PCR showed higher levels of IGFBP‐5 mRNA than any of the other known IGFBPs, suggesting that this was the major IGFBP subtype. The protein was subsequently identified by Western immunoblotting as IGFBP‐5. In conclusion, we postulate that this may be a mechanism contributing to the greater potency of ICI 182,780 in the growth inhibition of the MCF 7/5‐23, tamoxifen‐resistant cell line.
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    URL: http://dx.doi.org/10.1023/A:1006274712664
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  • 77
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    A study on the cost effectiveness of sestamibi scintimammography for screening women with dense breasts for breast cancer (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 243-258 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; cost effectiveness ; dense breasts ; mammographic parenchymal patterns ; Sestamibi scintimammography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The potential impact of Sestamibi scintimammography (SSMM) on the cost effective management of women with dense breasts is not known. This study addresses this issue quantitatively by examining the impact of SSMM based screening strategies on the ∼3,000,000 women over 40 with very dense breasts (DY patterns) without palpable masses and who have had one or more prior mammograms, who undergo routine screening each year. Quantitative decision tree sensitivity analysis was used to compare the conventional mammography (MM) strategy (strategy A), which does not subject patients with negative mammograms to any further examination until their next screening, with two decision strategies for screening with SSMM SSMM after a negative mammogram (strategy B) or SSMM as the only screening test for women already identified as having dense breasts by a previous mammogram (strategy C). Cost effectiveness was measured by calculating the incremental cost effectiveness ratio (ICER) of strategies B and C, which is the cost of achieving an additional year of life in the screening population by choosing a SSMM based decision strategy rather than the conventional strategy. Strategies B and C reduced the number of false negative diagnoses by 62% and 8%, respectively. The ICER was $632,000 and $3.18M per life year for strategy B and C, respectively. To be cost effective, the pre‐test probability of cancer in the study population must be greater than 3% for strategy B or the cost of SSMM must be less than $50 for strategy C. These results show the ICER of an SSMM based breast cancer screening strategy in the management of patients with dense breasts is not currently within the range (∼$50,000 per year life saved) of other commonly performed medical interventions that are considered cost effective.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006211817207
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  • 78
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    Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 25-34 
    Details
    ISSN: 1573-7217
    Keywords: aromatase inhibition ; breast cancer ; formestane ; GnRH agonist ; goserelin ; pharmacology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established second‐line hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with well‐established methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophin‐releasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was well‐tolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical–pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006289811540
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  • 79
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    Electronic Resource
    Hsp27 overexpression inhibits doxorubicin–induced apoptosis in human breast cancer cells (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 185-194 
    Details
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; doxorubicin ; hsp27 ; topoisomerase II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previously we demonstrated that heat shock protein 27 (hsp27) overexpression confers resistance to the chemotherapeutic agent doxorubicin in MDA–MB–231 breast cancer cells. Since induction of apoptosis is one underlying mechanism of chemotherapeutic drug action, we investigated the effect of hsp27 overexpression on doxorubicin–induced apoptosis, finding that hsp27 protects MDA–MB–231 cells from apoptosis. We also examined expression of the doxorubicin target, topoisomerase II (topo II), in control and hsp27–overexpressing stable transfectants, as topo II expression is important for both drug sensitivity and the initiation of apoptosis by doxorubicin. The relative levels of both topo IIα and β were higher in the controls than the hsp27–overexpressing clones, suggesting that the apoptotic protective effect of hsp27 overexpression in MDA–MB–231 cells is associated with altered topo II expression.abstract
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006207009260
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  • 80
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    pS2 (TFF1) levels in human breast cancer tumor samples: correlation with clinical and histological prognostic markers (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 251-263 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; mRNA ; pS2 ; prognostic marker ; RT–PCR ; TFF1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The expression of pS2 (TFF1) has been previously shown to identify patients with improved response to anti–hormonal therapy and more favorable outcome. In the current study, 100 human breast carcinoma samples obtained from the Manitoba Breast Tumor Bank were analyzed for pS2 mRNA using a quantitative, competitive reverse transcriptase–polymerase chain reaction (qcRT–PCR) assay. A pS2/ß–actin cut–off criterion of 0.010 was established to classify tumors as either pS2 positive or pS2 negative. pS2 mRNA levels were positively associated with both ER and PR, with the majority of ER+ (59) and PR+ (60) tumors also being positive for pS2. In addition, a significant linear correlation was observed between the amount of pS2 mRNA and ER (p〈0.0001) and PR (p〈0.0001) protein. pS2 mRNA levels also exhibited an inverse association with tumor size and histological grade, consistent with the observation that pS2 is primarily expressed in small (T 〈 2.0 cm), but well differentiated tumors (Grades I and II). No associations were observed with tumor cell type, patient age, or lymph node status. The strong correlation displayed between pS2 and a number of currently used breast cancer prognostic markers supports the clinical use of pS2 to further assess tumor status and patient outcome.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006215310169
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  • 81
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    Synergistic action of apoptosis induced by eicosapentaenoic acid and TNP‐470 on human breast cancer cells (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 147-158 
    Details
    ISSN: 1573-7217
    Keywords: angiogenesis inhibitor ; apoptosis ; Bcl‐2 ; breast cancer ; eicosapentaenoic acid ; TNP‐470
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of eicosapentaenoic acid (EPA) and an angiogenesis inhibitor (TNP‐470) on the suppression of breast cancer cell growth were examined in five human breast cancer cell lines (MDA‐MB‐231, T‐47D, MCF‐7, KPL‐1, and MKL‐F). In all five cell lines, EPA and TNP‐470 alone both showed tumor growth inhibition in a time‐ and dose‐dependent manner, and in combination, a synergistic effect was seen at high concentrations. EPA plus TNP‐470 treatment evoked apoptosis as confirmed by the appearance of sub G1 populations, by DNA fragmentation, and by cell morphology. With the combination, the expression of Bax and Bc1‐xS, the apoptosis‐enhancing proteins, was more up‐regulated and that of Bcl‐2 and Bcl‐xL, the apoptosis‐suppressing proteins, was more down‐regulated compared to the use of EPA or TNP‐470 alone, suggesting that their synergistic effect was due to an acceleration of apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006283131240
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  • 82
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    Electronic Resource
    Down‐regulation of gelsolin expression in human breast ductal carcinoma in situ with and without invasion (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 177-186 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; ductal carcinoma in situ (DCIS) ; gelsolin ; prognostic features
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Expression of gelsolin, an actin filament regulatory protein, in human breast ductal carcinoma in situ (DCIS) was analyzed by immunohistochemistry using a monoclonal antibody. Formalin‐fixed paraffin‐embedded tissues from 59 pure DCIS specimens and 33 DCIS specimens with associated invasive components were evaluated for gelsolin reactivity and compared to eight normal breast cases and 76 invasive breast cancers. The proportion of cases exhibiting negative/low expression of gelsolin in the epithelium was as follows – normal, 0%; pure DCIS, 56%; DCIS associated with invasion, 58% in the DCIS component and 66% in the invasive component; invasive carcinoma, 70%. These data demonstrate that down‐regulation of gelsolin expression in breast epithelium frequently parallels progression to malignancy. Testing gelsolin expression (normal vs. negative/low levels) in the DCIS lesions for associations with patient age or any of the following histopathologic parameters revealed no significant (95% probability level) correlations – tumor size; pathologic (Van Nuys system) grade; nuclear grade; necrosis; presence of histologic calcifications; presence or type of adjacent benign lesions; architectural histologic pattern; and mammographic extent. Gelsolin loss was more commonly associated with mammographic soft tissue lesions as compared to calcified lesions (P = 0.009). A positive trend of borderline significance (P = 0.06) found in the DCIS with invasion group was a correlation between down‐regulated gelsolin expression in the DCIS component and size (〈 versus ≥ 15 mm) of the invasive tumor. In conclusion, reduced gelsolin protein is detectable in at least half of breast lesions which have progressed to DCIS. The trend between increasing gelsolin loss and malignant progression from normal epithelium to DCIS to invasive breast cancer (P 〈 0.0001) suggests additional investigation is needed to determine the potential of altered gelsolin expression as a marker for prognosis and for therapeutic interventions in breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006203632228
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  • 83
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    Electronic Resource
    Anti‐human procathepsin D activation peptide antibodies inhibit breast cancer development (1999)
    Springer
    Breast cancer research and treatment 57 (1999), S. 261-269 
    Details
    ISSN: 1573-7217
    Keywords: activation peptide ; antibodies ; breast cancer ; immunotherapy ; procathepsin D
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Enzymatically inactive procathepsin D secreted from cancer cells has been confirmed to play a role in development of human breast cancer. In the present study, we focused on the role of activation peptide which was in our preliminary studies suggested to be most probably responsible for mitogenic activity of procathepsin D. Using synthetic fragments and antibodies raised against individual fragments, we demonstrated that the growth factor activity of activation peptide is localized in a nine amino acid stretch (AA 36–44) of activation peptide and moreover both anti‐activation peptide and anti‐ 27–44 peptide antibodies administered in vivo inhibited the growth of human breast tumors in athymic nude mice. Taking into account our previous results and presented data, we hypothesize that the interaction of procathepsin D activation peptide with an unknown surface receptor is mediated by a sequence 36–44 plus close vicinity. We also propose that this interaction leads in certain types of tumor derived cell lines to proliferation and higher motility. Blocking of the interaction of activation peptide by specific antibodies or antagonists might be a valuable tool in breast cancer inhibition.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006238003772
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  • 84
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    Coexpression of c-kit and stem cell factor in breast cancer results in enhanced sensitivity to members of the EGF family of growth factors (1999)
    Springer
    Breast cancer research and treatment 58 (1999), S. 1-10 
    Details
    ISSN: 1573-7217
    Keywords: Akt ; breast cancer ; c-kit ; EGF ; ERK ; heregulin ; stem cell factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Kit, a tyrosine kinase growth factor receptor, and its ligand, stem cell factor (SCF), are commonly coexpressed in breast cancer. We have previously shown that MCF7 cells (that naturally express SCF) transfected with a c-kit expression vector exhibit enhanced growth in serum-free medium supplemented with IGF-1. Consequently, we wished to examine the interaction of Kit/SCF with additional growth factors important in the biology of breast cancer. MCF7 transfectants expressing Kit, cultured in serum-free medium supplemented with EGF, displayed more than twice the growth of controls at identical EGF concentrations. Similar responses were seen in the presence of heregulin. The specificity of the Kit-mediated response was illustrated by a reduction in heregulin-stimulated growth in the presence of a monoclonal antibody directed against the Kit receptor. In addition, EGF- and heregulin-stimulated growth of the ZR75-1 cell line that naturally coexpresses Kit and SCF was also inhibited by the Kit blocking antibody. Preliminary investigations into the signal transduction pathways activated by these growth factors revealed that SCF activated both the Ras-MAP kinase and phosphatidyl-inositol-3-kinase (PI3 kinase) pathway. Both EGF and heregulin activated MAPK but to a lesser degree than SCF, and combination of SCF with these growth factors resulted in enhanced MAPK activation. Assessment of PI3K pathway activation using anti-phospho-Akt antibodies revealed that EGF was a poor activator of Akt; activation of this pathway was markedly enhanced by the addition of SCF. Heregulin activated Akt and addition of SCF provided no further activation. Taken together these results suggest that coexpression of SCF and Kit may enhance responsiveness to erbB ligands by enhancing activation of the MAPK and PI3K pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006272527435
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  • 85
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    Electronic Resource
    Hypermethylation of the Wilms' tumor suppressor gene CpG island in human breast carcinomas (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 35-43 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; CpG island ; DNA hypermethylation ; Wilms' tumor suppressor gene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract CpG island hypermethylation is known to be associated with transcriptional silencing of tumor suppressor genes in neoplasia. We have previously detected aberrantly methylated sites in the first intron of the Wilms' tumor suppressor (WT1) gene in breast cancer. In the present study, we extended the investigation to a CpG island located in the promoter and first exon regions of WT1. Methylation of this CpG island was found to be extensive in MCF‐7 and MDA‐MB‐231 breast cancer cells, as well as in 25% (five of 20 patients) of primary breast tumors. While levels of the known 3.0‐kb WT1 mRNAs were decreased or not detected in these cell lines, the expression could be partially restored following treatment with a demethylation agent, 5‐aza‐2′‐deoxycytidine. Surprisingly, a novel 2.5‐kb WT1 transcript was expressed at high levels in both untreated and treated MDA‐MB‐231 cells. This novel transcript was likely a WT1 variant missing the first exon, and therefore escaped the methylation control present in the normal transcript. Our study implicates the future need to investigate the significance of this aberrant transcript as well as the role of WT1 CpG island hypermethylation in breast neoplasia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006222803788
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  • 86
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    Electronic Resource
    Breast cancer and timing of surgery during menstrual cycle: a 5‐year analysis of 248 premenopausal women (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 259-266 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; menstrual cycle phase ; premenopausal ; prognosis ; surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present report, we retrospectively analyzed the impact of the timing of surgery during menstrual cycle on disease‐free and overall survival of 248 premenopausal patients with stage I/Il breast cancer who underwent surgery followed by anthracycline‐containing adjuvant chemotherapy. With a median follow‐up of 5 years, no statistically significant differences were observed in disease‐free or overall survival between women operated upon during the follicular (days 0–14) and the luteal (days 15–32) phase of the menstrual cycle. The impact on disease‐free and overall survival of lymph‐node status, tumor size and hormone receptor expression, but not of the phase of the menstrual cycle at the time of surgery, was confirmed by univariate and multivariate analysis. However, when combined with hormone receptor status, the phase of the menstrual cycle at the time of surgery proved useful to better define the prognosis of primary breast cancer patients, with significantly longer disease‐free and overall survival for patients operated upon during the follicular phase and with positive hormone receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006276120841
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  • 87
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    Early age at menopause and breast cancer: are leaner women more protected? A prospective analysis of the Dutch DOM cohort (1999)
    Springer
    Breast cancer research and treatment 55 (1999), S. 285-291 
    Details
    ISSN: 1573-7217
    Keywords: body mass index ; breast cancer ; menopause ; smoking
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To investigate the relationship between age at menopause, body mass index, and breast cancer risk, we used data from a prospective cohort study (DOM cohort) in the Netherlands. Participants in this breast cancer‐screening project included 10,591 women living in Utrecht, aged 49–66 years at enrolment. During a median follow‐up period of 19 years, women attended screening rounds at which anthropometric measurements were taken and questions were asked about menopausal status, age at menopause, medication use and other risk factors for breast cancer. Cox regression analysis was used to investigate the relationship between age at menopause and subsequent breast cancer risk. Breast cancer incidence decreased with an earlier age at menopause. Women with a menopausal age of 44 years or younger had a 34% lower risk of breast cancer, than women with a menopausal age over 54 years (hazard ratio is 0.66 (95% confidence interval 0.43–0.91)). The annual hazard of breast cancer incidence decreased by 2.6% per year reduction in age at menopause. The protective effect of an early age at menopause was stronger for women with a low body mass index (≤27 kg/m2; reduction of 44%) than for women with a high body mass index (〉27 kg/m2; reduction of 24%), although this difference was not statistically significant (P for interaction = 0.58). This difference was most pronounced in women who had ever smoked. Adjustment for known breast cancer risk factors did not alter the crude risk estimates significantly. In conclusion, this study provides evidence of the protective effect of lower age at menopause on subsequent breast cancer risk. This protective effect may be even stronger in leaner women.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006277207963
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  • 88
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    Suppression of parathyroid hormone‐related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 11-23 
    Details
    ISSN: 1573-7217
    Keywords: androgen receptor ; bone metastasis ; breast cancer ; medroxyprogesterone acetate ; parathyroid hormone‐related protein ; progesterone receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The level of parathyroid hormone‐related protein (PTHrP) expressed in breast cancer tissue is closely related to the incidence of bone metastasis. We examined the PTHrP mRNA expression in breast cancer tissues by coamplification polymerase chain reaction (PCR) in mole ratio to internal standard β‐actin mRNA. The PTHrP expression was higher in premenopausal patients than in postmenopausal patients (P〈0.05). More pronounced difference by menopause found in estrogen receptor (ER) positive groups (P〈0.001) indicated that the PTHrP expression in breast cancer tissue is hormonally regulated and might be altered by endocrine agents. To clarify the changes of PTHrP expression by endocrine therapy of breast cancer, we measured PTHrP expression in the breast cancer tissue incubated for 24 h with 1 × 10−8 M of estradiol (E2), 1 × 10−6 M of tamoxifen (TAM) and 1 × 10−5 M of medroxyprogesterone acetate (MPA). The PTHrP expression was decreased significantly by MPA (P〈0.005), while E2 and TAM did not change the PTHrP expression. Progesterone receptor (PgR) mRNA expression was also examined to confirm that the breast cancer tissue responds to E2 and TAM. The results were well compatible with the better therapeutic effect of MPA reported for the treatment of breast cancer with bone metastases. As a potential candidate for the receptor that mediates the suppressive effect of MPA, androgen receptor (AR) is suggested most probable. Present results also demonstrated that the clinical response of individual tumors is closely associated with the early in vitro changes of gene expression detected in the cancer specimen.
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    URL: http://dx.doi.org/10.1023/A:1006254006088
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  • 89
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    Quality of life in the first year after breast cancer surgery: rehabilitation needs and patterns of recovery (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 45-57 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; psychological distress ; quality of life ; rehabilitation needs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Although mortality rates from breast cancer are declining, many breast cancer survivors will experience physical and psychological sequelae that affect their everyday lives. Few prospective studies have examined the rehabilitation needs of newly diagnosed breast cancer patients, and little is known about the predictors of health‐related quality of life (QOL) in this population. Methods. Between 1987 and 1990, 227 women with early stage breast cancer participated in a prospective longitudinal study in which detailed information was collected through interviews, standardized measures of QOL and psychological distress, and clinical evaluation. Comparisons of physical and treatment‐related problems were made according to type of surgical treatment. Multivariate regression analysis was performed to examine the predictors of QOL at one year after surgery. Results. Physical and treatment‐related problems were reported frequently one month after breast cancer surgery, and occurred with equal frequency in women receiving modified radical mastectomy or breast conservation treatment. There were no significant differences in problems reported at one year by type of surgery; however, frequently reported problems include ‘numbness in the chest wall or axilla,’ ‘tightness, pulling or stretching in the arm or axilla,’ ‘less energy or fatigue,’ ‘difficulty in sleeping,’ and ‘hot flashes’. There was no relationship between the type of surgery and mood or QOL. Poorer QOL one year after surgery was significantly associated with greater mood disturbance and body image discomfort one month after surgery, as well as positive lymph node involvement. Although the majority of patients experienced substantial disruptions in the physical and psychosocial dimensions of QOL post‐operatively, most women recovered during the year after surgery, with only a minority (〈10%) significantly worsening during that time. Conclusions. At one year after surgery, most women report high levels of functioning and QOL, with no relationship between the type of surgery and QOL. Women who reported lower levels of QOL at one year after diagnosis had greater mood disturbance and poorer body image one month after surgery, as well as lower income and positive axillary nodes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006214830854
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  • 90
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    Postoperative chemo–endocrine treatment with mitomycin C, tamoxifen, and UFT is effective for patients with premenopausal estrogen receptor–positive stage II breast cancer (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 111-122 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; estrogen receptor ; mitomycin C ; postoperative chemotherapy ; tamoxifen ; UFT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effectiveness of combining mitomycin C (MMC), tamoxifen (TAM), and 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) was evident in patients with estrogen receptor-positive (ER+) breast cancers. UFT, an oral preparation of tegafur and uracil at a molar ratio of 1:4, was reported to have higher antitumor effects than tegafur alone for patients with breast cancer. Therefore, the combined chemotherapy of MMC, TAM and UFT may possibly be effective for breast cancer. From 1988 to 1991, we studied the effects of postoperative adjuvant therapy for Japanese women with stage II breast cancer, all seen at 71 institutions in western areas of Japan. Five hundred and ninety four patients with stage II primary breast cancer who had undergone curative surgery, including total mastectomy and axillary lymph node dissection, were enrolled. On the day of surgery, each patient was given 13 mg/m2 of MMC intravenously. Patients with ER+ tumors were then assigned to group A or group B. Group A received 30 mg/day of TAM given orally from postoperative 2 weeks, for 2 years. Group B was additionally given an oral dose of 300 mg/day of UFT for 2 years, given concomitantly with 30 mg/day of TAM. Patients with ER− tumors were assigned to group C or group D. Group C were prescribed 300 mg/day of UFT, orally, from postoperative 2 weeks for 2 years, and group D were additionally given an oral dose of 30 mg/day of TAM together with 300 mg/day of UFT. There were no differences among the groups regarding prognostic factors or doses of MMC and TAM in ER+ patients and MMC and UFT in ER− patients. Toxicity rates for leukopenia, anorexia, and nausea/vomiting were higher in group B than in group A patients. There were no statistical differences in the overall survival and disease–free survival times between groups A and B, or groups C and D, for all eligible cases. In a retrospective subgroup analysis using Bonferroni's adjustments, the additional effect of UFT on the combined treatment of MMC and TAM lengthened the disease-free survival time for patients with premenopausal ER+ cancers (corrected P value by Bonferroni's adjustments 〈0.05). Multivariate analysis showed that effects of the combined treatment of MMC, TAM, and UFT was significantly related to the menopausal status (P〈0.0 1). Our findings show that postoperative ingestion of MMC, TAM, and UFT was effective for patients with premenopausal ER+ stage II breast cancer.
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    URL: http://dx.doi.org/10.1023/A:1006221425652
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  • 91
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    Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 143-149 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; immunohistochemistry ; nitric oxide synthases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Expression of inducible nitric oxide synthase (iNOS) by tumor cells has been suggested to abrogate metastasis in several tumor models, whereas constitutive NOS expression correlated positively with tumor grade in human breast carcinoma. Whether or not expression of one of the various NOS isoforms could predict the prognosis of breast cancer, however, has not been established. In the present report we investigated the cellular distribution of NOS isoforms in a series of benign and malignant breast tumors and in normal breast tissue. Immunohistochemistry revealed that in samples of benign disease the number of iNOS + epithelial cells or total epithelial cells was 69 ± 16% (n=50). In samples of grade II invasive ductal breast carcinomas the number of iNOS+ tumor cells or total tumor cells was 62 ± 20 (n=40), compared to 12 ± 9 (n=40) in samples of grade III carcinomas (P 〈 0.0001). iNOS protein was also identifiable in most of the epithelial cells of normal breast tissue (n=4). In contrast, eNOS protein was restricted to vascular endothelial cells in all of the specimens studied. Since the presence of tumor cell iNOS protein is inversely related to the tumor’s metastatic potential, we conclude that endogenous tumor cell mediated iNOS expression might have an inhibitory effect on the metastatic process in breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006288526311
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  • 92
    Electronic Resource
    Electronic Resource
    PACAP (6–38) is a PACAP receptor antagonist for breast cancer cells (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 175-184 
    Details
    ISSN: 1573-7217
    Keywords: PACAP ; VIP ; breast cancer ; proliferation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of pituitary adenylate cyclase activating polypeptide (PACAP) analogs were investigated using breast cancer cells. 125I–PACAP–27 bound with high affinity (Kd=5 nM) to T47D cells (Bmax = 29,000 per cell). Specific 125I–PACAP–27 binding was inhibited half maximally by PACAP–27, PACAP–38, PACAP(6–38) and PACAP(28–38) with IC50 values of 8, 17, 750 and 〉3000 nM, respectively. By RT–PCR, PACAP receptor mRNA was present in MCF–7 and T47D cell lines. Polyclonal antibodies to a PACAP receptor fragment (A–8–C) were elicited. The antibodies were affinity purified, recognized a 60–kDa protein by western blot, and stained malignant cells in breast cancer biopsy specimens by immunohistochemistry. PACAP–27 elevated the cAMP in T47D cells and the increase in cAMP caused by PACAP was inhibited by PACAP(6–38). PACAP–27 stimulated c–fos mRNA in T47D cells and the increase in c-fos gene expression caused by PACAP was reversed by PACAP (6–38). PACAP (6–38) inhibited colony formation using a soft agar assay and inhibited breast cancer xenograft growth in nude mice. These data suggest that PACAP (6–38) functions as a breast cancer PACAP receptor antagonist.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006262611290
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  • 93
    Electronic Resource
    Electronic Resource
    Changes in body composition during breast cancer chemotherapy with the CMF‐regimen (1999)
    Springer
    Breast cancer research and treatment 57 (1999), S. 285-290 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; chemotherapy ; CMF ; weight gain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Weight gain is a reported problem associated with adjuvant chemotherapy for breast cancer and often generates psychosocial stress in women [1]. It also may affect prognosis and survival. Changes in body composition and weight during chemotherapy, particularly adjuvant treatment of breast carcinoma, have been previously reported [1–3]. Multiple reasons for this weight gain have been suggested though few theories have been scientifically validated [4]. The aim of this study was to investigate body composition and its relationship to weight change associated with the CMF‐based breast cancer chemotherapy protocols. Total body nitrogen (TBN), body fat, total body water (TBW), and anthropometric measurements were conducted on 25 female out‐patients (median age 47, range 26–70 years) receiving adjuvant CMF‐based chemotherapy for breast cancer. Total body nitrogen was measured using the In Vivo Neutron Capture Analysis (IVNCA) technique (on day 1 of cycles 2–6) and TBP was calculated by multiplying TBN by 6.25 [5]. Nitrogen Index (NI) was calculated by expressing TBN as a percentage of normal. There was a significant increase in mean body weight during chemotherapy of 2.35 kg (p〈0.0001). Serial measurements showed no significant change in mean TBN, NI, or percentage body fat. Break down of body weight showed a significant increase in mean TBW of 0.79 kg (p=0.003) and mean fat mass of 1.49 kg (p=0.008). We conclude that weight gain observed during adjuvant chemotherapy for breast carcinoma is primarily due to an increase in fat and TBW.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006220510597
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  • 94
    Electronic Resource
    Electronic Resource
    Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c‐erbB and retinoic acid receptor expression in MCF‐7 breast cancer cells (1999)
    Springer
    Breast cancer research and treatment 58 (1999), S. 171-181 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; c‐erbB ; cross‐talk regulation ; RAR ; retinoid ; steroid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Nuclear steroid/thyroid/retinoid receptors and c‐erbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple c‐erbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via cross‐connected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and c‐erbB‐2, and between ER and retinoic acid receptor(RAR)‐α have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12‐O‐tetradecanoylphorbol‐13‐acetate, TPA), on growth and expression of c‐erbB and RARs in MCF‐7 breast cancer cells, which contain high levels of RAR‐α and ‐γ, and which express significant amounts of c‐erbB‐2 and ‐3. All trans‐retinoic acid (tRA), the anti‐estrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17β‐estradiol (E2) stimulated cell growth. Flow cytometry revealed that tRA and E2 reduced c‐erbB‐2 and ‐3, whereas tamoxifen, Forsk and TPA up‐regulatedc‐erbB‐2. c‐erbB‐3 was co‐regulated with c‐erbB‐2. Northern analysis demonstrated that RAR‐α was down‐regulated by dexamethasone, ICI, and TPA, whereas vitamin D3 and E2 up‐regulated RAR‐α. RAR‐γ expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and c‐erbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006377006816
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  • 95
    Electronic Resource
    Electronic Resource
    Quantitation of erbB-2 gene copy number in breast cancer by an improved polymerase chain reaction (PCR) technique, competitively differential PCR (1999)
    Springer
    Breast cancer research and treatment 58 (1999), S. 211-215 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; gene amplification ; polymerase chain reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A new method of measuring gene copy number in small samples of DNA was used to measure amplification of the erbB-2 gene and a reference gene in breast cancers. The method, termed 'competitively differential polymerase chain reaction' (CD-PCR), combines the advantages of two other techniques for measuring amplification by PCR, namely differential PCR (D-PCR) and competitive PCR (C-PCR). The CD-PCR methodology was evaluated for sensitivity and specificity by comparing amplification measured by CD-PCR with that obtained by fluorescence in situ hybridization (FISH), C-PCR, and Southern blotting analysis. CD-PCR analysis proved to be an accurate predictor of amplification. CD-PCR also overcomes the problems involved in variation of PCR efficiencies and DNA concentrations in tumor samples, and the problems caused by the plateau effect in PCR.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006367700783
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  • 96
    Electronic Resource
    Electronic Resource
    Influence of estrogen receptor variants on the determination of ER status in human breast cancer (1999)
    Springer
    Breast cancer research and treatment 58 (1999), S. 217-223 
    Details
    ISSN: 1573-7217
    Keywords: estrogen receptor variant mRNAs ; estrogen receptor status ; immunohistochemistry ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Determination of estrogen receptor alpha (ER) status in breast cancer is an important predictive factor for clinical response to endocrine therapy. We have recently shown that discrepancies in ER status determined by immunohistochemical assay (ER-IHA) can occur between amino-terminal (1D5) and carboxyl-terminal (AER-311) targeted ER antibodies and that those tumors which demonstrate discordance are associated with increased expression of truncated ER variant mRNAs. In this study, we have explored this observation to examine if ER variant expression can exert a direct effect on ER-IHA or whether this association is attributable to the characteristics of the antibodies. ER negative cos-1 cells were transfected with expression vectors containing wild type ER (wt-ER) and/or a frequently expressed truncated variant, ER-clone-4 variant. We found that ER-IHA performed with the same N- and C-terminal targeting ER antibodies on cos-1 cells expressing wt-ER alone demonstrated no difference in signals by western blot (P〉0.1). However, co-expression of wt-ER and the truncated ER-clone-4 variant, resulted in discordant IHA results with relatively higher ER-IHA H-scores from N-terminal antibodies (P〈0.03). Furthermore, re-examination of a subset of breast tumors previously studied by ER-IHA showed persistent concordance in 4/5 cases and persistent differences in 3/5 cases with a different pair of ER antibodies. We conclude that the presence of truncated ER variant proteins can interfere with the interpretation of ER status determined by IHA and that this may account for some of the inconsistencies between ER status and response to endocrine therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006375902601
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  • 97
    Electronic Resource
    Electronic Resource
    Occupational physical activity and risk for breast cancer in a nationwide cohort study in Sweden (1999)
    Springer
    Cancer causes & control 10 (1999), S. 423-430 
    Details
    ISSN: 1573-7225
    Keywords: breast cancer ; physical activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: Our purpose was to investigate effects of physical activity on risk for breast cancer. Methods: From the Swedish nationwide censuses in 1960 and 1970 we defined three partly overlapping cohorts of women whose occupational titles allowed reproducible classification of physical demands at work in 1960 (n=704,904), in 1970 (n=982,270), or with the same demands in both 1960 and 1970 (n=253,336). The incidence of breast cancer during 1971–89 was ascertained through record linkage to the Swedish Cancer Register. We used Poisson regression to estimate relative risks (RR). Results: A total of 20,419, 22,840, and 8261 breast cancers, respectively, were detected in the three cohorts. In all three cohorts the risk for breast cancer increased monotonically with decreasing level of occupational physical activity and with increasing socioeconomic status. Among women with the same estimated physical activity level in 1960 and 1970 the RR was 1.3 for sedentary as compared with high/very high activity level (95% CI 1.2–1.4; p for trend〈0.001). Adjustment for socioeconomic status virtually eliminated this association (RR 1.1; 95% CI 0.9–1.2; p for trend 0.12) leaving a statistically significant 30% gradient only among women aged 50–59 years at follow-up. The association between socioeconomic status and breast cancer risk was largely unchanged after adjustment for occupational physical activity. Conclusion: The protective effect of occupational physical activity on breast cancer risk, if any, appears to be confined to certain age groups.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008922205665
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  • 98
    Electronic Resource
    Electronic Resource
    Microvessel density and vascular basement membrane immunostaining in tumours of the breast (1999)
    Springer
    Angiogenesis 3 (1999), S. 175-180 
    Details
    ISSN: 1573-7209
    Keywords: angiogenesis ; breast cancer ; collagen IV ; heparan sulphate proteoglycan ; laminin ; vascular basement membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is a well established correlation between increased breast tumour microvessel density (MVD) and reduced prognosis. The aims of this study were to investigate (1) if MVD is elevated in regions other than `hotspots' of node positive versus node negative breast tumours, and (2) to quantitate the percentage of vessels without vascular basement membrane (VBM) components in high vascular density (HVD) and average vascular density (AVD) regions of node positive and node negative breast tumours. Serial sections were immunostained for CD31 and double-stained for CD31 and collagen IV (CollIV), laminin (LAM) or heparan sulphate proteoglycan (HSPG). Microvessel counts were obtained from HVD and AVD regions and the number of VBM positive vessels were expressed as a percentage of total CD31 positive vessels. MVD was significantly higher in both the HVD and AVD regions of node positive compared with node negative breast tumours (t-test; P 〈 0.03). The average percent vessels positive for CollIV, LAM or HSPG ranged from 18%–45% and did not differ between node positive and negative breast tumours (t-test; P 〉 0.05). No differences were observed in VBM immunostaining between regions of HVD and AVD (t-test; P 〉 0.05). These results demonstrate that vascular density is elevated throughout node positive breast tumours, rather than just in `hotspots', and show that there is no apparent difference in the percentage of VBM-naked vessels in node positive versus node negative breast tumours.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009035123733
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  • 99
    Electronic Resource
    Electronic Resource
    The methodology of quantitation of microvessel density and prognostic value of neovascularization associated with long‐term survival in Japanese patients with breast cancer (1999)
    Springer
    Breast cancer research and treatment 53 (1999), S. 19-31 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; long‐term survival ; microvessel density ; neovascularization ; quantitation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study updates results on methodology of quantitation of tumor neovascularization and those on the prognostic value of microvessel density (MVD) in breast cancer tissue previously published in the World J. Surg. 21: 49–56, 1997. The follow‐up period of observation of the series was extended to 20 years, and new biological indicators (i.e., proliferating cell nuclear antigen (PCNA), c‐erbB‐2, and p53) were included in the analysis. There were 109 patients with primary breast cancer, from 1971 to 1979, followed up for a median of 14 years (range, 1–20). A representative median longitudinal section of each breast tumor was immunohistochemically stained with factor VIII‐related antigen and analyzed. The three methods of identifying MVD were: (1) average microvessel count (AMC)/mm2, (2) central microvessel count (CMC)/mm2, and (3) highest microvessel count (HMC)/mm2. Thirty‐one patients (28.4%) died of breast cancer. There was a relationship between MVD and peritumor blood vessel invasion (AMC: p = 0.0114, CMC: p = 0.0319, and HMC: p = 0.0009). However, there was no relationship between MVD and other factors. Univariate analysis showed that node status (p 〈 0.0001), histological grade (p 〈 0.0001), clinical tumor size (T) (p = 0.0002), PCNA (p = 0.0033), p53 (p = 0.0043), mitotic grade (p = 0.0092), AMC (p = 0.0214), and peritumor lymphatic vessel invasion (p = 0.0467) were significantly predictive of overall survival. HMC was borderline significant (p = 0.0702), while CMC and c‐erbB‐2 were not significant. Multivariate analysis showed that T (p = 0.0005), node status (p = 0.0053), and AMC (p = 0.0485) were independent factors, but neither CMC nor HMC was independent. AMC, a significant independent prognostic factor, might be a better method than the others for evaluating angiogenesis, but further and larger studies are warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006193024382
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  • 100
    Electronic Resource
    Electronic Resource
    Prognostic factors in patients with isolated recurrences of breast cancer (stage IV-NED) (1999)
    Springer
    Breast cancer research and treatment 53 (1999), S. 105-112 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; combined modality therapy ; isolated recurrences ; radiation therapy ; surgery ; systemic therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: One to 10% of women with metastatic breast cancer have a recurrence of their disease as an isolated lesion (local, regional, or distant) which may be treated by surgical resection, irradiation, or both. These are patients with stage IV breast cancer with no evidence of disease, or stage IV-NED. Because natural history and prognostic factors for patients with stage IV-NED are poorly determined, we decided to evaluate a group of patients with stage IV-NED treated at a single institution. Patients and methods: Ninety-six patients with isolated recurrence of stage IV breast cancer were analyzed retrospectively. Treatment of loco-regional or distant recurrence was surgery in 18 patients and surgery plus irradiation in 78 patients. Seventy-nine patients received systemic therapy after loco-regional treatment (24 chemotherapy and 55 hormonotherapy). Prognostic factors were analyzed and correlated with disease-free survival (DFS) and overall survival (OS). Results: Five-year DFS and OS for the whole group were 29% and 49% respectively. On the univariate analysis, patients without axillary nodal involvement at the time of mastectomy had significantly greater 5-year DFS and OS than patients with nodal involvement (51% vs. 14% and 70% vs. 34% respectively, p〈 0.05). DFS was also significantly better for patients receiving systemic therapy after local treatment (31% vs. 19%). On the multivariate analysis, absence of nodal involvement and systemic therapy were associated with longer DFS (p = 0.044 and p = 0.008, respectively) and OS (p = 0.009 and p = 0.011, respectively). None of the other factors analyzed including menopausal status, T-stage, number of involved nodes, receptor status, adjuvant therapy, sites of first recurrence, or time from mastectomy to first recurrence had a predictive value for DFS and OS. Conclusion: Patients with stage IV-NED have poor prognosis due to early development of metastatic disease. Absence of axillary nodal involvement at the time of mastectomy and systemic therapy following local management is associated with improved DFS and OS. These results suggest that systemic therapy after local treatment in stage IV-NED is indicated. Poor prognosis in patients with previous nodal involvement warrants new approaches.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006090319083
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