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  • 1995-1999  (6,480)
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  • apoptosis
  • breast cancer
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  • 1995-1999  (6,480)
  • 1985-1989
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  • 1
    Electronic Resource
    Electronic Resource
    Apoptosis as a Prognostic Factor in Colorectal Carcinoma (1998)
    Springer
    Surgery today 28 (1998), S. 145-150 
    Details
    ISSN: 1436-2813
    Keywords: Key Words: colorectal carcinoma ; apoptosis ; Ki-67 ; p53 ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: P 〈 0.05); in tumors showing evidence of moderate differentiation than in well-differentiated tumors (P 〈 0.05); and in tumors with venous invasion or lymph node metastasis than in those without these features (P 〈 0.05). Moreover, the subgroup of patients with a low AI of 〈4.1 had a significantly poorer survival rate than the subgroup with a high AI in tumors at Dukes stage C, the 5-year survival rates being 33% vs 68% (P 〈 0.05; Cox-Mantel). Our findings suggest that less apoptosis might result in a greater progression of colorectal carcinoma, and that the rate of apoptosis might be an indicator of the degree of malignancy. Thus it would appear that the frequency of apoptosis in tumor cells could be a useful prognostic factor in colorectal carcinoma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005950050096
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  • 2
    Electronic Resource
    Electronic Resource
    Histological Evaluation of the Effects of Intraarterial Chemotherapy for Advanced Breast Cancer: A Long-term Followup Study with Respect to the Survival Rate (1998)
    Springer
    Surgery today 28 (1998), S. 509-516 
    Details
    ISSN: 1436-2813
    Keywords: Key Words: intraarterial chemotherapy ; breast cancer ; histological response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005950050175
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  • 3
    Electronic Resource
    Electronic Resource
    p53 Protein Overexpression as a Predictor of the Response to Chemotherapy in Gastric Cancer (1998)
    Springer
    Surgery today 28 (1998), S. 595-598 
    Details
    ISSN: 1436-2813
    Keywords: Key Words: gastric cancer ; chemosensitivity ; p53 ; bcl-2 ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: P = 0.013). Tissue from 3 of the responders and 7 of the nonresponders that stained for bcl-2 were positive prior to chemotherapy; however, there was no association between bcl-2 staining and chemotherapeutic effect. In conclusion, immunohistochemical identification of p53 in pretreatment tissue may represent a useful predictor for chemotherapeutic outcome in patients with gastric cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005950050190
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  • 4
    Electronic Resource
    Electronic Resource
    Seroma with Fibrous Capsule Formation Requiring a Surgical Resection After a Modified Radical Mastectomy: Report of a Case (1998)
    Springer
    Surgery today 28 (1998), S. 669-672 
    Details
    ISSN: 1436-2813
    Keywords: Key words: seroma ; breast cancer ; mastectomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005950050206
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  • 5
    Electronic Resource
    Electronic Resource
    Effect of trans-retinoic acid and folic acid on apoptosis in human gastric cancer cell lines MKN-45 and MKN-28 (1998)
    Springer
    Journal of gastroenterology 33 (1998), S. 656-661 
    Details
    ISSN: 1435-5922
    Keywords: Key words: gastric cancer cell lines ; apoptosis ; retinoic acid ; folic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: Induction of apoptosis has been implicated as an anticarcinogentic mechanism of both folic acid and retinoic acid. The ability of retinoic acid or folic acid to induce gastric cancer cell apoptosis was investigated in the human gastric cancer cell lines MKN-45 and MKN-28, and DNA fragmentation was studied in situ by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and DNA agarose gel electrophoresis. The rates of apoptosis in both the poorly differentiated MKN-45 and the well differentiated MKN-28 cell line were less than 5% after treatment with either retinoic or folic acid. Apoptosis may be induced by the administration of retinoic acid or folic acid, and the apoptosis indices of MKN-45 and MKN-28 cells were related to the doses of these drugs. The induction of gastric cancer cell apoptosis may play a role in the anticarcinogenetic effect of retinoic acid and folic acid, both of which are potential agents for the treatment of human gastric cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005350050152
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  • 6
    Electronic Resource
    Electronic Resource
    Abdominal pain with anorexia in patients with breast carcinoma (1998)
    Springer
    Annals of oncology 9 (1998), S. 1243-1245 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; gastrointestinal metastases ; invasive lobular carcinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Breast cancer is the second commonest primary tumour responsible for gastrointestinal metastases after malignant melanoma. The real incidence of gastrointestinal metastases in breast cancer patients is probably underestimated owing to the non-specific presenting symptoms and death of patients caused by other more obvious metastases. The predominant histological subtype of gastrointestinal metastases of breast cancer is invasive lobular carcinoma and the median interval from diagnosis of primary breast cancer to gastrointestinal metastases is five years. We report two cases of disseminated breast cancer with gastrointestinal involvement with a rather long survival.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008287007819
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  • 7
    Electronic Resource
    Electronic Resource
    The anti-proliferative effect of suramin towards tamoxifen-sensitive and resistant human breast cancer cell lines in relation to expression of receptors for epidermal growth factor and insulin-like growth factor-I: Growth stimulation in the presence of tamoxifen (1998)
    Springer
    Annals of oncology 9 (1998), S. 205-211 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; epidermal growth factor ; insulin-like growth factor-I ; suramin ; transforming growth factor-β
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: A significant proportion of breast cancer patients receiving tamoxifen therapy relapse during treatment following acquisition of tamoxifen-resistant or oestrogen-independent phenotypes. The mechanism behind this rapid progression to oestrogen autonomy is at present unclear and further treatment modalities are limited. Suramin represents a novel potential second line therapy. The mechanism of the antineoplastic activity of suramin is not completely understood, although the drug binds to many growth factors including epidermal growth factor and insulin-like growth factors and can also dissociate growth factors from their receptors. In this study we have related suramin sensitivity to the expression of receptors for epidermal growth factor and insulin-like growth factor-I in a number of breast cancer cell lines including lines resistant to tamoxifen. Materials and methods: The anti-proliferative effects of suramin were investigated in two oestrogen dependent breast cancer lines (ZR-75-1 and MCF-7), oestrogen independent (ZR-PR-LT) and tamoxifen resistant (ZR-75-9a1) variants of ZR-75-1 and a tamoxifen resistant (LY2) variant of MCF-7. Full dose response curves were constructed and IC50values determined for each cell line. Sensitivity to suramin was correlated with the level of expressio n of receptors for epidermal growth factor (EGFR) and insulin-like growth factor-I (IGFR). On observing stimulation of cell proliferation by suramin in the tamoxifen resistant cell lines in the presence of tamoxifen we also investigated the possible role of suramin sequestration of transforming growth factor-β in mediating this effect. Results: All cell lines exhibited a dose- and time-dependent response to suramin treatment. Tamoxifen resistant ZR-75-9a1 cells (day 6 IC5085 µg ml−1) were more resistant to suramin than oestrogen independent ZR-PR-LT cells (day 6 IC5045 µg ml−1), and the parent ZR-75-1 line (day 6 IC5056 µg ml−1). Increased sensitivity to suramin was associated with increased expression of IGFR and decreased expression of EGFR. Tamoxifen resistant LY2 cells were significantly more sensitive to suramin (day 6 IC5070 µg ml−1) than MCF-7 cells (day 6 IC50350 µg ml−1). Both IGFR and EGFR expression by LY2 cells was lower than in the parent line. The antioestrogen-resistant ZR-75-9a1 and LY2 lines grown in the presence of 8 µM tamoxifen were growth stimulated by concentrations of the drug below 100 µg/ml. As growth stimulation observed in the presence of tamoxifen may have been due to suramin sequestration of tamoxifen induced TGF-β1 secretion we also investigated the response of the cells to this peptide in the presence and absence of suramin. All cell lines were growth inhibited by TGF-β1 except ZR-75-9a1 which was unresponsive. Responses to TGF-β1 were modified in the presence of 100 µg suramin ml−1 although TGF-β1 was unable to mimic the ability of tamoxifen to stimulate proliferation in the presence of suramin. Conclusions: These results suggest that for ZR-75-1 cells and variants, increased sensitivity to suramin is associated with an increase in expression of IGFR and a decrease in EGFR numbers. However, tamoxifen resistant LY2 cells, in which both IGFR and EGFR expression is reduced were considerably more sensitive than parental MCF-7 cells suggesting that there is no clear relationship between EGFR and IGFR expression and suramin sensitivity. The unexpected stimulation of cell proliferation of the tamoxifen resistant variants by suramin in the presence of tamoxifen could not be explained by suramin sequestration of transforming growth factor-β and the mechanism of this interaction remains unclear.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008241804078
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  • 8
    Electronic Resource
    Electronic Resource
    Dosage of adjuvant G-CSF (filgrastim)-supported FEC polychemotherapy based on equivalent haematological toxicity in high-risk breast cancer patients (1998)
    Springer
    Annals of oncology 9 (1998), S. 403-411 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant ; breast cancer ; G-CSF (filgrastim) ; individualized chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Conventional dosages of cytostatics in mg/m2 will cause marked variations in systemic exposure, resulting in over- and under-treatment, at least with respect to side effects. Patients and methods: We are conducting a randomized adjuvant study for breast cancer patients younger than 60 years of age with ≥70% risk of recurrence within five years. The first 89 consecutive patients who have received nine courses q three weeks of individually dose-escalated and G-CSF (filgrastim)-supported FEC (5-fluorouracil (5-FU), epirubicin, and cyclophosphamide) therapy given with ciprofloxacin prophylaxis were included in this analysis. Six different FEC dose levels were used for treatment at equivalent haematological toxicity. Dose modifications were based on white blood cell and platelet counts on days 8, 11/12, 15, and 22. Results: Eighty-three of 89 patients completed all nine courses. The median epirubicin and cyclophosphamide doses were 782 mg/m2 (range 0–994 mg/m2) and 10.330 mg/m2 (range 0–14.460 mg/m2), respectively. Patients treated at the two highest dose levels experienced NCI grade 0 or 1 toxicities in 73% to 92% of the courses. Three patients have developed acute myeloid leukaemia, and two of them have demonstrated abnomalities compatible with topoisomerase II-poison-related karyotypic changes. Conclusions: Tailored adjuvant G-CSF-supported FEC polychemotherapy will make it possible for all patients to be treated at equivalent levels of haematological toxicity with significantly higher doses without a marked increase in other organ toxicities.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008252014312
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  • 9
    Electronic Resource
    Electronic Resource
    Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: Are all CMFs alike? (1998)
    Springer
    Annals of oncology 9 (1998), S. 489-493 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant chemotherapy ; breast cancer ; CMF ; radiotherapy ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The first reported effective adjuvant combination regimen for patients withoperable breast cancer comprised oral cyclophosphamide (C) days 1–14with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8,repeated every 28 days (’classical‘ CMF). These drugs have since beenextensively used with or without endocrine therapies and/or other cytotoxics,as well as with radiation therapy to the chest wall yielding conflictingresults. Although doses and schedules have varied widely, the combination ofthese three drugs has been generically referred to as CMF. Evidence existsthat reducing the dose and/or altering the schedule of CMF (’modified‘ CMF)have compromised its efficacy in metastatic breast cancer. Reduction belowstandard dose of a similar regimen also gave inferior results in the adjuvantsetting. In fact, the recently reported improved outcome of adding radiationtherapy to CMF was only demonstrated in comparisons with a ’modified‘ CMF.Furthermore, trials in women with estrogen receptor-positive breast cancer,which did not demonstrate any significant benefit for the addition of adjuvantCMF to tamoxifen compared with tamoxifen alone, also used ’modified‘ CMF.Therefore, adherence to the ’classical‘ dose and schedule is recommended whenCMF is used in adjuvant therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008236502420
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  • 10
    Electronic Resource
    Electronic Resource
    Hematopoietic progenitor cell collection and neoplastic cell contamination in breast cancer patients receiving chemotherapy plus granulocyte-colony stimulating factor (G-CSF) or G-CSF alone for mobilization (1998)
    Springer
    Annals of oncology 9 (1998), S. 913-916 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; G-CSF ; mobilization ; stem cells ; transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: We compared hematopoietic progenitor cell (HPC) collection and neoplastic cell contamination in breast cancer patients given cyclophosphamide (CTX) plus granulocyte-colony stimulating factor (G-CSF) or G-CSF alone for mobilization. Patients and methods: In 57 stage II–III breast cancer patients, CD34+ cells, colony-forming units-granulocyte macrophage (CFU-GM), early HPC and breast cancer cells were counted in HPC collections obtained after CTX plus G-CSF (n = 27) or G-CSF-alone mobilization (n = 30). Results: The CD34+ cell collection was about two-fold greater after CTX plus G-CSF mobilization (11.0 ± 7.9 vs. 5.8 ± 3.5 × 106/kg, P 〈 0.001). Similarly, the total number of CFU-GM, CD34+CD38− cells and of week-5 cobblestone area forming cells (CAFC) collected was significantly higher in patients mobilized with CTX plus G-CSF. Breast cancer cells were found in the apheresis products of 22% of patients mobilized with CTX plus G-CSF and in 10% of patients mobilized with G-CSF alone (P = 0.36). Of seven patients who failed G-CSF-alone mobilization and eventually underwent chemotherapy plus G-CSF mobilization, none had cytokeratin-positive cells after G-CSF mobilization, whereas four out of seven had cytokeratin-positive cells after chemotherapy plus G-CSF (P = 0.07 by χ2 test). Conclusion: The CTX plus G-CSF mobilization protocol was associated with a significantly higher HPC collection. However, this benefit was not accompanied by a reduction in the incidence of tumor-contaminated HPC graft.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008226428543
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  • 11
    Electronic Resource
    Electronic Resource
    Minimal residual disease in autologous hematopoietic harvests from breast cancer patients (1998)
    Springer
    Annals of oncology 9 (1998), S. 821-826 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; high-dose chemotherapy ; minimal residual disease ; stem cell transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The increasing use of high-dose chemotherapy with autologous hematopoietic transplantation for the treatment of solid malignancies has raised concern about the role of tumor cells contaminating the grafts. Minimal residual disease (MRD) in autologous grafts has became a dynamic and intensively studied field in oncology. This review discusses the current status of MRD in breast cancer autografts and presents existing data on detection methodology, clinical relevance, biologic characteristics and purging techniques.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008344708061
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  • 12
    Electronic Resource
    Electronic Resource
    Recommendations for medical management of hereditary breast and ovarian cancer: The French National Ad Hoc Committee (1998)
    Springer
    Annals of oncology 9 (1998), S. 939-950 
    Details
    ISSN: 1569-8041
    Keywords: BRCA1 ; BRCA2 ; breast cancer ; guidelines ; ovarian cancer ; preventive care
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background and purpose: Almost 10% of breast and ovarian cancers are familial, and the majority are linked to BRCA1 and BRCA2 germline mutations. Despite uncertainty about the management of female gene carriers, consensus guidelines have been established to assist practitioners and consultees in making health care decisions. Methodology: The Ad Hoc Committee was composed of 14 experts appointed by the French National Institute for Health and Medical Research, all of whom attended eleven workshops at which more than 3500 articles were systematically analyzed. Five additional experts critically analysed the first version of the report. Criteria and decision process: On a probability scale of the risk of developing breast or ovarian cancers, two thresholds were defined for use in determining whether an intervention would be worthwhile. The first is the threshold above which an intervention can be envisaged or recommended, and the second is the one below which an intervention can be ruled out; between the two, the decision has to be made on a case-by-case basis. Screening and preventive strategies analyzed: With respect to breast cancer: 1) hormonal interventions; 2) primary prevention (diet, family planning and chemoprevention); 3) screening (breast self-examination, clinician breast examination, tumor markers, imaging); 4) prophylactic mastectomy. With respect to ovarian cancer: 1) hormonal stimulation; 2) screening (clinical screening, ultrasound and tumor markers); 3) prophylactic oophorectomy. Main conclusions: For each strategy the following points were addressed: the information to be given to the consultee, the procedure and the indications. In addition, the committee's opinion about BRCA1 and BRCA2 mutation screening is that population-based, or even large-scale, implementation are not justified. Although no scientific evidence is available, the committee feels that specific management is indispensable and advocates the use of defined and evaluated procedures, and participation in clinical trials.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008389021382
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  • 13
    Electronic Resource
    Electronic Resource
    First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): A phase II study conducted by the Hellenic Cooperative Oncology Group (1998)
    Springer
    Annals of oncology 9 (1998), S. 1031-1034 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; carboplatin ; chemotherapy ; paclitaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC). Background: Paclitaxel is an active agent in ABC. Furthermore, our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC. Patients and methods: From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg × min/ml every three weeks. The median age of the patients was 56 years (range 28–75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. Results: A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5–69.3) and the relative DI was 0.95 (range 0.5–1.2). Eight patients (12%, 95% confidence interval (CI): 5%–22%) achieved complete and 28 (42%, 95% CI: 30%–55%) partial responses. Grade 3–4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1,5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07–24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07–23+) months and median survival 20.4 (range 0.07–24.5+) months. Conclusions: The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008466928323
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  • 14
    Electronic Resource
    Electronic Resource
    No evidence of significant activity of the multidrug resistance gene product in primary human breast cancer (1998)
    Springer
    Annals of oncology 9 (1998), S. 85-93 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; MDR1 gene ; multidrug resistance ; P-glycoprotein ; rhodamine 123
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The discovery of the multidrug resistance (MDR1) gene product P-glycoprotein (P-gp) has been widely seen as an important milestone in our understanding of the mechanisms underlying the clinical phenomenon of the emergence of resistant cells. MDR1 expression has been shown for numerous solid tumors and for virtually all hematologic malignancies. Nevertheless, results regarding MDR1/P-gp expression in human breast cancer have been controversial and the results of clinical trials on modulation of P-gp activity have not been encouraging. Patients and methods: MDR1/P-gp expression and the function of the P-gp pump were investigated in 61 tumor samples from patients with primary breast cancers by multiparameter analysis using MDR1-RT-PCR, immunohistochemistry with two MAbs (UIC2 and MRK 16) and the rhodamine 123 (Rh123) efflux assay. The cellular composition of the tumor cell suspension was analyzed by using specific MAbs against the P-gp expressing lymphocyte subsets CD4, CD8 and CD56, as well as against the HER-2/neu gene product, which was used to identify breast carcinoma cells. Results: UIC2 and MRK16 revealed a staining positivity in 72% and 75% of samples, respectively. A positive MDR1-RT-PCR signal was detected in 62% of the samples. Nevertheless, no correlation between immunohistochemistry and RT-PCR could be established. Furthermore, there was no correlation between HER-2/neu expression and MDR1-RT-PCR or P-gp immunohistochemical assays. A contamination by CD8+ and CD4+ lymphocytes was established in 100% and 84% of tumor cell suspensions, respectively. As assessed by the Rh123 efflux assay CD8+ and the CD4+ lymphocytes exhibited marked P-glycoprotein activity, whereas such activity was not detectable in a single instance for the breast carcinoma cells. In MDR1-RT-PCR positive samples, contamination by CD8 lymphocytes averaged 4.3%, while the contamination of CD8 cells in the MDR1 mRNA-negative samples was only 2.4% (P = 0.007). This signal vanished after elimination of the lymphocyte subpopulations by T-cell rosetting. Conclusions: In primary breast cancer detection of MDR1 gene expression by means of RT-PCR or immunohistochemical assays is not indicative for the MDR phenotype, since there is no evidence of significant activity of the P-gp pump.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008255725515
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  • 15
    Electronic Resource
    Electronic Resource
    Recent advances in the molecular genetics of cancer (1998)
    Springer
    Annals of oncology 9 (1998), S. 23-29 
    Details
    ISSN: 1569-8041
    Keywords: apoptosis ; cancer ; molecular genetics ; multistep progression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The second joint conference of the AACR and the EACR held in Oxford from9–12 September 1997 was successful from many vantage points. While providing an optimal setting in which European and American cancer researchers could meet and exchange information, the conference had an excellent scientific programme which encompassed both methodological updates on important models used in cancer research and presentations of recent key advances in the molecular genetics of cancer. Lower eukaryotes are established model organisms used to elucidate fundamental but complex eukaryotic processes, such as those involved in tumorigenesis and cancer progression, and the progressive availability of their genome sequence makes them even more attractive. Transgenic mouse models are increasingly used not only for the study of one gene of interest but for investigation of the interactions among genes involved in the same pathway. The family of tumour suppressor genes is growing fast and several presentations were devoted to recently identified members such as the Von Hippel–Lindau gene, the FHIT gene and the PTEN gene. The systematic analysis of loss of heterozygosity on multiple loci in tumour specimens can provide the basis for preliminary models of molecular multistep progression in some tumour types, even though this is limited by the high degree of complexity found. Mechanisms of cell cycle regulation and apoptosis continue to be dissected and to constitute a fruitful area of investigation, with important recent insights on the p53-MDM2 autoregulatory loop and on the involvement of E2F-1 in apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008263531395
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  • 16
    Electronic Resource
    Electronic Resource
    A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer (1998)
    Springer
    Annals of oncology 9 (1998), S. 1179-1184 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; chemotherapy ; mastectomy ; neoadjuvant ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Backgound: A prospective randomised trial was undertaken to evaluate the role of neoadjuvant chemoendocrine therapy prior to surgery in primary operable breast cancer. Patients and methods: Three hundred nine women (median age 56 years, range 27–70) with primary operable breast cancer confirmed on fine needle aspiration (FNA) cytology were recruited to this study. They were treated with a combination of mitozantrone and methotrexate (± mitomycin-C) combined with tamoxifen (2MT). Patients received eight cycles of 2MT (four prior to surgery in the neoadjuvant group) and tamoxifen for five years with appropriate surgery and radiotherapy. The two groups were comparable for age, menopausal status, stage and surgical requirements. Results: The clinical response rates to neoadjuvant therapy were as follows: 22% complete response (CR), 29% minimal residual disease (MRD), 33% partial response (PR), 15% no change (NC) and only two patients had clinical evidence of progressive disease. Surgical requirements were reduced from 31 patients (22%) of the adjuvant group having mastectomy to 14 (10%) in the neoadjuvant group (P 〈 0.003). At a median follow-up of 48 months (range 10–70 months) there is no statistically significant difference between the two groups in terms of local relapse, metastatic relapse or overall survival. Symptomatic and haematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. Conclusion: This randomised trial has shown a significant reduction in the surgical requirements for mastectomy, after treatment with neoadjuvant chemoendocrine therapy, with no deterioration in local or distal relapse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008400706949
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  • 17
    Electronic Resource
    Electronic Resource
    Clinical course of breast cancer patients with metastases confined to the lungs treated with chemotherapy (1998)
    Springer
    Annals of oncology 9 (1998), S. 413-418 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; chemotherapy ; lungs ; metastases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To evaluate the clinical course of patients with a metastatic breast cancer (MBC) confined to the lungs and treated with doxorubicin/cyclophosphamide-containing chemotherapy (DC-CT). Patients and methods: Between 1973 and 1985, 1581 patients with MBC were treated with DC-CT at M.D. Anderson Cancer Center. Data for 88 patients (5.6%) with metastases confined to the lungs were reviewed to correlate various clinical characteristics with response to treatment and survival. Results: The overall response rate was 76% with 33% achieving complete response (CR). The median overall survival time was 22 months (range 1–210). The 10-year survival rate was 9%. The overall response and CR rates were higher for the patients with metastases confined to the lungs (76% and 33%, respectively) than for the remainder of MBC patients (64% and 14%; P 〈 0.01). The 10-year survival rate was also higher (9% versus 3%, P 〈 0.01), but there were no differences in median overall survival rate. Conclusions: This retrospective analysis demonstrated that patients with metastases confined to the lungs treated with DC-CT had a high objective response rate, especially high CR rates, and a median survival comparable to that of our entire population of MBC patients. A small but clinically significant percentage of patients had prolonged survival. Therefore, not all visceral sites are indicators of poor prognosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008205522875
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  • 18
    Electronic Resource
    Electronic Resource
    New treatments for breast cancer: Breakthroughs for patient care or just steps in the right direction? (1998)
    Springer
    Annals of oncology 9 (1998), S. 973-976 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant paclitaxel ; breast cancer ; Herceptin™ ; prevention ; Raloxifene ; Tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three areas of clinical research in breast cancer treatment led to news breaking presentations at the American Society of Clinical Oncology (ASCO) meeting, 1998, in Los Angeles. All three subjects represent important advances in cancer medicine. Prevention: Two related drugs, tamoxifen and raloxifene, were found in placebo controlled trials to significantly reduce the incidence of breast cancer for women at increased risk of developing the disease. Patterns of relapse showed that the reduced rate of breast cancer was exclusively observed for tumors expressing estrogen receptors, while the rate of tumors classified as estrogen-receptor negative was similar for the treatment and the control groups. This may indicate that the observed reduction in breast cancer incidence is due to a treatment effect on occult disease rather than its prevention. We certainly have no adequate information on mortality prevention. Adjuvant therapies: Taxol given every three weeks for four courses following an adjuvant treatment with four courses of doxorubicin and cyclophosphamide (AC) combination was found to be superior to not adding treatment after the four courses of AC in a trial involving 3170 patients. At 22 months of median follow-up, the quoted P-values were P = 0.0077 for disease-free survival and P = 0.039 for overall survival, but these did not cross the prospectively defined interim analysis boundaries for statistical significance at the 0.05 level. The difference was observed early during follow-up, and was exclusively seen in the 40% of patients who had ER-negative primaries and, therefore, did not receive tamoxifen following chemotherapy. One may thus argue that the early difference observed was primarily due to differences in the duration of the treatment regimens in the two groups and the early entry into the trial of patients with particularly aggressive neoplasia (e.g., ER-negative primaries) who would have benefited from a longer duration treatment. Treatment of advanced disease: The use of monoclonal antibodies to c-erb-B2 was found to induce responses in metastatic breast cancer. Patients with tumors expressing c-erb-B2 responded to weekly infusions of this biological agent. It was particularly impressive that the response rate for patients receiving infusion of the monoclonal antibodies together with the cytotoxics was superior to that with chemotherapy alone in a randomized trial. It is important to note that only patients with tumors overexpressing c-erbB-2 (the overall incidence is about 20%) were tested. It must still be demonstrated that the effect of these monoclonal antibodies is indeed confined to cells overexpressing c-erbB-2. Treatment related cardiac toxicity remains a problem, and the effects of treatment in various subsets of patients need to be defined before starting investigations in the adjuvant setting, which is a clear further objective of this specific research. The significant findings from clinical research opened several new questions, which must be answered before allowing them to be employed in routine patient care.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008436810268
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  • 19
    Electronic Resource
    Electronic Resource
    The role of calcium in apoptosis (1998)
    Springer
    BioMetals 11 (1998), S. 375-382 
    Details
    ISSN: 1572-8773
    Keywords: apoptosis ; programmed cell death (PCD) ; calcium ; DAP-Kinase ; calcineurin ; ALG-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract In this chapter various aspects of apoptosis or programmed cell death (PCD) influenced by calcium as a mediator of signal transduction have been reviewed. Attention has been focused on recently described calcium-binding proteins such as ALG-2 or on a new calcium/calmodulin-dependent kinase, the death asso-ciated protein kinase or DAP-kinase. Both play a central role in apoptotic processes. Calcineurin, which normally is involved in the regulation of T-cell proliferation, is reported to interact with the apoptosis protec-tion protein bcl-2. Its possible involvement in the decision process whether T-cell activation leads to prolif-eration or apoptosis is discussed.© Kluwer Academic Publishers
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009226316146
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  • 20
    Electronic Resource
    Electronic Resource
    Apoptosis and scarring (1998)
    Springer
    Clinical and experimental nephrology 2 (1998), S. 302-306 
    Details
    ISSN: 1437-7799
    Keywords: apoptosis ; kidney ; scarring ; glomerulosclerosis ; extracellular matrix
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Conclusion The results suggest that basement membrane matrix, as compared with type I collagen or fibronectin matrix, prevents mesangial cells from undergoing apoptosis and promotes the survival of mesangial cells after serum deprivation or H2O2 treatment. This indicates that matrix composition infuences susceptibility to proapoptotic stimuli for mesangial cells, and is involved in the control of cell survival and death. We have summarized our hypothesis in Fig. 4. Accumulation of extracellular matrix and progressive cell loss are the most prominent features of glomerulosclerosis. Extracellular matrix components are altered both quantitatively and qualitatively in the process leading to sclerosis. Altered matrix components may influence the susceptibility of mesangial cells to apoptotic stimuli, such as ROS. In such a situation, glomerular cells are easily lost by apoptosis. The mechanism of glomerular cell apoptosis requires further study to enable researchers to gain new insights into the treatment of renal diseases and the prevention of subsequent glomerular scarring.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02480458
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  • 21
    Electronic Resource
    Electronic Resource
    Glucocorticoid-induced apoptosis of rat mesangial cells in culture (1998)
    Springer
    Clinical and experimental nephrology 2 (1998), S. 12-17 
    Details
    ISSN: 1437-7799
    Keywords: mesangial cell ; apoptosis ; glucocorticoid ; cell culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background Apoptosis of glomerular mesangial cells is shown in experimental and human glumerulonephritis. But it is unclear whether or not glucocorticoids can induce apoptosis in mesangial cells. Methods Rat mesangial cells in culture were incubated with dexamethazone and methylprednisolone. Apoptosis was evaluated by DNA-specific staining with fluorescent dye (H33258), in situ nick end labeling, gel electrophoresis of extracted DNA, and electron microscopy. Results The proportion of lysed cells and cells positive for nick end labeling increased at a concentration of 0.2 to 5 mmol/L of dexamethazone and methylprednisolone. Chromatin condensation and DNA ladders in those cells were also seen. Actinomycin D, a transcriptional inhibitor, or cycloheximide, a translational inhibitor, partially blocked glucocorticoid-induced apoptosis of rat mesangial cells. Conclusions Glucocorticoids induced typical apoptosis in rat mesangial cells. These data provide new information on the pharmacologic action of glucocorticoids on mesangial cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02480618
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  • 22
    Electronic Resource
    Electronic Resource
    Protection of islet allografts transplanted together with Fas ligand expressing testicular allografts (1998)
    Springer
    Diabetologia 41 (1998), S. 315-321 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Fas ; Fas ligand ; islet transplantation ; testicular tissue ; apoptosis ; composite graft.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Fas ligand (FasL) is highly expressed in testicular tissues and thought to be responsible for protection from allograft rejection by inducing apoptosis of anti-graft activated T cells. FasL-expressing islets have been shown to induce a granulocyte-mediated inflammatory reaction. We investigated whether a graft can be protected from alloimmune responses by manipulating the Fas/FasL-system. We transplanted allogeneic islets under the kidney capsule of streptozotocin-induced diabetic mice together with testicular tissue. Significant prolongation of survival of C3H islet allograft was observed in C57BL/6 (B6) recipients transplanted with C3H testicular tissue, but not in those transplanted with C3H-gld testicular tissue expressing non-functional FasL. No significant prolongation was observed in B6-lpr recipients expressing non-functional Fas. Immunohistochemical staining of C3H testicular tissue in the composite graft showed a high expression of FasL, but not that of the C3H-gld testicular tissue. In situ terminal deoxynucleotidyl transferase-mediated dUDP-biotin catalysed DNA nick-end labelling (TUNEL) staining of a composite graft of C3H islet and testicular tissue in B6 recipients demonstrated extensive apoptosis of infiltrating mononuclear cells around the graft. The protective effect of C3H testicular tissue was abrogated when anti-FasL monoclonal antibody was administered i. p. postoperatively. Our results suggest that FasL-positive testicular allografts protect composite islet allografts and indicate that manipulation of Fas/FasL mediated apoptosis is a suitable strategy for controlling rejection of islet allografts. [Diabetologia (1998) 41: 315–321]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050909
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  • 23
    Electronic Resource
    Electronic Resource
    Ultrasound in vascular pathologies (1998)
    Springer
    European radiology 8 (1998), S. 849-857 
    Details
    ISSN: 1432-1084
    Keywords: Key words: Ultrasound ; Physics ; Vascular studies ; Vascular pathologies ; Ultrasonic contrast agents ; Clinical applications
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The choice of the optimal ultrasonic frequency for vascular studies is determined by the required resolution and penetration. Anatomical real-time two-dimensional imaging and blood flow studies provide complementary information. Intravascular scanning allows high-frequency ultrasound to be used, with correspondingly good spatial resolution. Contrast resolution is degraded by beam side lobes and the limited dynamic range of the ultrasonic pulse. The physics of ultrasonic scattering by blood, pulsed Doppler and duplex scanning and colour flow imaging performances determines the limits of clinical applications. Contrast agents enhance the echogenicity of blood, improving sensitivity and, through second harmonic detection, suppressing solid tissue echoes. Three-dimensional display, with segmentation by the presence of the flow signal, facilitates spatial perception. Clinical applications in vascular pathologies are summarised.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003300050482
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  • 24
    Electronic Resource
    Electronic Resource
    The changing landscape of breast cancer clinical research (1998)
    Springer
    Annals of oncology 9 (1998), S. 133-138 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; clinical research ; molecular biology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Clinical research for breast cancer is moving in three new directions following: 1) a critical analysis of three decades of randomized clinical trials for early disease; 2) increasing awareness of this lethal disease among women, generating women's associations which are pressing for improved breast cancer education, screening and treatment; 3) an exponential growth in our understanding of breast cancer molecular biology, leading to a number of innovative therapies with new targets in the cancer cell or its environment. It is the remarkable work of the Oxford Group which has finally vindicated the use of our three main weapons against breast cancer micro-metastases, namely tamoxifen, chemotherapy and ovarian ablation. There is now consensus that clinical research in the adjuvant setting may gain speed and efficiency through intergroup collaboration. Such an 'Intergroup' has been recently created in Europe and will collaborate with the American–Canadian Intergroup. Women's associations have only recently stepped forward to demand better care, and more effective therapies: they are becoming new partners in identifying critical issues in breast cancer research. Medical oncologists involved in breast cancer research are facing a new challenge: the optimal integration of traditional breast cancer therapies, namely endocrine treatments and chemotherapy, and entirely new strategies targeting signal transduction, apoptosis or angiogenesis. In view of the above, there is no doubt that we are entering a new and exciting era in breast cancer clinical research.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008257824361
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  • 25
    Electronic Resource
    Electronic Resource
    Staging of breast cancer: What standards should be used in research and clinical practice? (1998)
    Springer
    Annals of oncology 9 (1998), S. 1173-1177 
    Details
    ISSN: 1569-8041
    Keywords: bone scan ; breast cancer ; chest radiography ; liver ultrasonography ; risk groups ; staging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Bone scan (BS), chest X-rays (CXR), liver ultrasonography (LUS) and laboratory parameters (LP) are frequently used as routine staging procedures for breast cancer patients. These procedures are not always appropriate in either clinical or research settings, regardless of the stage. The aim of this study was to identify groups of patients with differing risks for metastases in order to select more precise standard staging procedures. Patients and methods: The staging data relating to 406 breast cancer patients consecutively referred to our institution between November 1989 and October 1996 were analysed including pathological TNN grading and biological parameters. All of the cases with a positive or suspicious pre-operatory staging and who proved to have metastatic disease before surgery or during the first six months of follow-up were considered true- positive; all of the other cases with a positive or suspicious initial staging but with no evidence of distant metastasis before surgery and with a disease-free survival longer then six months were considered false-positive. In the same way all cases with negative initial staging who relapsed during the first six months of follow-up were considered false-negative and those with negative initial staging and with a disease-free survival longer then six months were considered true-negative. Statistical analysis was performed using Fisher's exact test. Results: BS, CXR and LUS, 388, 399 and 398 examinations respectively, were considered available, and 17 (4.38%), six (1.5%) and four (1%), respectively, proved to be true-positive. A statistically significant difference was observed when our cases were grouped according to T status (T4 vs. T1–T2–T3, P 〈 0.01) and nodal status (N0–N1 cases with less than three involved nodes and N1 with more than three positive lymph nodes N2 patients, P 〈 0.01). Conclusions: The present study suggests that breast cancer patients can be divided into three subgroups with different detection rates for distant metastases at staging (0.59%, 2.94% and 15.53%), and that the standard practice should be changed. In the first (T1N0 and T1N1 patients with ≤3 positive lymph nodes – 41.13% of the patients) and the second group (T2N0, T2N1 with ≤3 positive lymph nodes, T3N0 and T3N1 patients with ≤3 positive lymph nodes – 33.49% of the patients) there is no need for a complete set of staging procedures, whereas full procedural staging is needed in the third group of patients (T4, N1 with 〉3 lymph nodes and N2, 25.37% of the patients).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008483806113
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  • 26
    Electronic Resource
    Electronic Resource
    Biological effects of a relatively low concentration of 1-b-D-arabinofuranosylcytosine in K562 cells: Alterations of the cell cycle, erythroid-differentiation, and apoptosis (1998)
    Springer
    Molecular and cellular biochemistry 187 (1998), S. 211-220 
    Details
    ISSN: 1573-4919
    Keywords: 1-β-D-arabinofuranosylcytosine ; cell cycle ; apoptosis ; differentiation ; K562 cells ; c-myc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Therapeutic strategies for leukemia are directed to induction of differentiation and apoptosis as well as growth inhibition. One of the key antileukemic agents, 1-β-D-arabinofuranosylcytosine (ara C), is clinically applied according to these therapeutic aims. However, the molecular effects of 0.1 μg/ml of ara C, a concentration that corresponds to the serum level in leukemic patients on a conventional dose of ara C, have not been well disclosed. Here, we addressed these issues using K562 cells which derived from a blastic crisis of chronic myeloid leukemia. DNA synthesis of treated cells was suppressed from 1-6 h. But, it recovered at 12 h and no further inhibition was observed. The number of cells was not decreased but DNA fragmentation was observed at 72 h. The number of erythroid-differentiated cells also increased to 30% at 72 h. Along with treatment, no marked alteration of mRNAs for cell cycle-regulating genes was found and the retinoblastoma gene product remained hyperphosphorylated throughout treatment. The expression of mRNAs for apoptosis-regulating genes also remained unchanged, except for slight down-regulation of Bax. c-myc protein was not found later than 48 h, and Max mRNA was downregulated. c-jun was immediately induced, followed by the fluctuated expression level along with treatment. These findings suggest that the 0.1 μg/ml ara C changed the proliferation, differentiation and death of K562 cells in a biphasic manner. In the early phase, DNA synthesis was inhibited without altering the expression of cell cycle regulating-genes. In the latter phase, cell death and erythroid- differentiation occurred in accordance with the down-regulation of c-myc.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006874931249
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  • 27
    Electronic Resource
    Electronic Resource
    Apparent cleavage of poly(ADP-ribose) polymerase in non-apoptotic mouse LTA cells: An artifact of cross-reactive secondary antibody (1998)
    Springer
    Molecular and cellular biochemistry 178 (1998), S. 245-249 
    Details
    ISSN: 1573-4919
    Keywords: poly(ADP-ribose) polymerase ; apoptosis ; word ; antibody cross-reactivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Proteolytic cleavage of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) to fragments of 89 kD and 24 kD is widely observed during apoptotic cell death. In the present study, labelling of a Mr ∼89000 polypeptide was demonstrated in untreated mouse LTA cells during probing of immunoblots with C-2-10 monoclonal anti-PARP antibody. The source of the labeling was traced to the secondary antibody preparation, which labeled a Mr ~89000 polypeptide in murine LTA cells but not in human cells. These observations indicate that assessment of PARP cleavage must be (1) performed with appropriate controls when new cell lines are investigated and (2) carefully interpreted in light of additional biochemical or morphological data demonstrating apoptotic changes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006808001462
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  • 28
    Electronic Resource
    Electronic Resource
    Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant (1998)
    Springer
    Molecular and cellular biochemistry 186 (1998), S. 159-168 
    Details
    ISSN: 1573-4919
    Keywords: ischemia ; dedifferentiation ; apoptosis ; chronic hibernating myocardium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Left ventricular biopsies from 21 patients with clinically diagnosed chronic hibernating myocardium (CHM) were examined by light- and electron microscopy. A mean of 27% of cardiomyocytes were structurally altered and were characterized as hibernating, because of reduced amount of myofibrils and increased glycogen content. Electron microscopy of these cells showed reduction of T-tubules and numerous small mitochondria, but few changes associated with degeneration, acute ischemia or apoptosis. The structural changes found in CHM are reminiscent of dedifferentiation rather than degeneration. The expression patterns of some structural proteins show resemblance with those in embryonic cardiomyocytes. Histochemically, mitochondrial NADH-oxidase and proton translocating ATPase activities were absent, whereas cytochrome c activity was present. Intracellular calcium distribution indicated normally bound sarcolemmal calcium and absence of excess mitochondrial calcium accumulation. Nuclear chromatin ranged from normal to dispersed with only a few nuclei that were clumped. These results suggest that cardiomyocytes from human CHM hearts are structurally altered, but viable, and lack morphologic and cytochemical characteristics suggestive of apoptosis or acute ischemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006887803970
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  • 29
    Electronic Resource
    Electronic Resource
    Dissociation of vitamin D3 and anti-estrogen mediated growth regulation in MCF-7 breast cancer cells (1998)
    Springer
    Molecular and cellular biochemistry 188 (1998), S. 13-20 
    Details
    ISSN: 1573-4919
    Keywords: vitamin D ; anti-estrogens ; apoptosis ; MCF-7 cells ; cell cycle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Our studies have identified 1,25(OH)2D3 as a coordinate regulator of proliferation and apoptosis in breast cancer cells. In MCF-7 cells, 1,25(OH)2D3 down regulates the estrogen receptor (ER), suggesting that the effects of 1,25(OH)2D3 may be linked to disruption of estrogen regulated survival signals. Although studies have demonstrated that 1,25(OH)2D3 inhibits growth of ER negative breast cancer cells, previous data were generated by comparison of cell lines derived from heterogeneous human tumors and harboring diverse genetic alterations. To provide more conclusive evidence for independent growth regulatory pathways mediated by antiestrogens and 1,25(OH)2D3, we examined vitamin D3 sensitivity in MCF-7 cells selected for resistance to ICI 182, 780 (Zeneca, Macclesfield, UK). The clones we selected for resistance to ICI 182,780 retain functional VDR and undergo 1,25(OH)2D3 mediated growth arrest and apoptosis, in vitro and in vivo, despite loss of estrogen dependence. Cell cycle data indicate that treatment of parental or anti-estrogen resistant MCF-7 clones with 1,25(OH)2D3, in the presence or absence of ICI 182,780, increases the percentage of cells in G0G1 while reducing the number of cells in S phase. In addition, 1,25(OH)2D3 induces characteristic features of apoptosis, including DNA fragmentation, in both parental and anti-estrogen resistant MCF-7 cells. Furthermore, we report that cells selected for vitamin D3 resistance retain sensitivity to ICI 182,780 mediated growth arrest and apoptosis. This work emphasizes that vitamin D3 compounds and anti-estrogens trigger growth arrest and apoptosis in breast cancer cells by distinct mechanisms, and that breast cancer cell sensitivity to 1,25(OH)2D3 is not diminished during the progression to estrogen independence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006879213501
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  • 30
    Electronic Resource
    Electronic Resource
    Timing of dietary fat exposure and mammary tumorigenesis: Role of estrogen receptor and protein kinase C activity (1998)
    Springer
    Molecular and cellular biochemistry 188 (1998), S. 5-12 
    Details
    ISSN: 1573-4919
    Keywords: breast cancer ; estrogen ; dietary fat ; polyunsaturated fatty acid ; estradiol ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during the fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a highfat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in tne serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high fat diet. Furthermore, the administration of estradiol to pregnant dams produce effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters' breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006827229431
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  • 31
    Electronic Resource
    Electronic Resource
    Targets of oxidative stress in cardiovascular system (1998)
    Springer
    Molecular and cellular biochemistry 187 (1998), S. 1-10 
    Details
    ISSN: 1573-4919
    Keywords: oxidant ; cardiovascular system ; signal transduction ; calcium ; mitogen activated protein kinases ; nuclear transcription factors ; tyrosine kinase ; protein kinase C ; superoxide ; hydrogen peroxide ; ischemia-reperfusion ; atherosclerosis ; phospholipases ; apoptosis ; antioxidant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Although oxidants such as superoxide (O2.-) and hydrogen peroxide (H2O2) play a role in host-mediated destruction of foreign pathogens yet excessive generation of oxidants may lead to a variety of pathological complications in the cardiovascular system. An important mechanism by which oxidants cause dysfunction of the cardiovascular system appears to be due to the increase in intracellular free Ca2+ concentration. Oxidants cause cellular Ca2+ mobilization by modulating activities of a variety of regulators such as Na+/H+ and Na+/Ca2+ exchangers, Na+/K+ ATPase and Ca2+ ATPase and Ca2+ channels that are associated with Ca2+ transport in the plasma membrane and the sarco(endo)plasmic reticular membrane of myocardial cells. Recent research have suggested that the increase in Ca2+ level by oxidants plays a pivotal role in indicing several protein kinases such as protein kinase C, tyrosine kinase and mitogen activated protein kinases. Oxindant-mediated alteration of different signal transduction systems and their interations eventually regulate a variety of pathological conditoins such as atherosclerosis, apoptosis and necrosis in the myocardium
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006802903504
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  • 32
    Electronic Resource
    Electronic Resource
    Chemical hypoxia triggers apoptosis of cultured neonatal rat cardiac myocytes: Modulation by calcium-regulated proteases and protein kinases (1998)
    Springer
    Molecular and cellular biochemistry 178 (1998), S. 141-149 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; cardiomyocyte ; azide ; hypoxia ; word ; calpain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Myocardial infarctions and stroke arise primarily as a result of hypoxia/ischemia-induced cell injury. However, the molecular mechanism of cardiac cell death due to hypoxia has not been elucidated. We showed here that chemical hypoxia induced by 1 mM azide triggered apoptosis of isolated neonatal rat ventricular cardiac myocytes but had no effect on cardiac fibroblasts. The azide-induced cardiomyocyte apoptosis could be characterized by a reversible initiation phase (0-6 h after azide exposure) during which cytosolic ATP levels remained little affected. This was followed by an irreversible execution phase (12-18 h) exhibiting prominent internucleosomal DNA fragmentation, cell membrane leakage, mitochondrial dysfunction, and increased calpain messenger RNA. Blocking extracellular calcium influx or intracellular calcium release was each effective in suppressing myocyte apoptosis. Cell death was also found to be mediated by calcium sensitive signal transduction events based on the use of specific antagonists. Consistent with the induction of calpain expression during apoptosis, blocking de novo protein synthesis and calpain activity inhibited cell death. These regulatory features coupled with the ease of the cell system suggest that the myocyte apoptosis model described here should be useful in the study of events leading to the demise of the myocardium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006893528428
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  • 33
    Electronic Resource
    Electronic Resource
    Biochemical and molecular mechanisms regulating apoptosis (1998)
    Springer
    Molecular and cellular biochemistry 178 (1998), S. 9-25 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; programmed cell death ; signal transduction ; CD95 (Fas) ; p53 ; c-myc ; bcl-2 ; caspases ; DNA fragmentation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract In eukaryotes, the regulation of tissue cell numbers is a critical homeostatic objective that is achieved through tight control of apoptosis, mitosis and differentiation. While much is known about the genetic regulation of cell growth and differentiation, the molecular basis of apoptosis is less well understood. Genes involved in both cell proliferation and apoptosis reflect the role of some stimuli in both of these processes, the cell response depending on the overall cellular milieu. Recent research has given fascinating insights into the complex genetic and molecular mechanisms regulating apoptosis. A picture is emerging of the initiation in certain cells, after an apoptotic trigger, of sequential gene expression and specific signal transduction cascades that guide cells along the cell death pathway. Changes in gene expression precede the better known biochemical and morphological changes of apoptosis. It seems possible that, as a result of increased understanding of the cellular events preceding cell death, apoptosis may become more amenable to manipulation by appropriate drug- and gene-based therapies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006891430596
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  • 34
    Electronic Resource
    Electronic Resource
    The salubrious effect of tamaxifen on serum marker enzymes, glycoproteins, and lysosomal enzymes level in breast cancer women (1998)
    Springer
    Molecular and cellular biochemistry 185 (1998), S. 85-94 
    Details
    ISSN: 1573-4919
    Keywords: tamoxifen ; breast cancer ; marker enzymes ; glycoproteins ; lysosomal enzymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Tumour markers correlate strongly with prognosis based on tumour burden and surgical resectability. If chemotherapy is extremely effective in certain stage of the disease, the sensitive marker may be of great use in monitoring disease response and drug treatment. Hence, this study was launched to evaluate the changes in tumour marker enzymes like lactate dehydrogenase (LDH), glumate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase, and acid phosphatase in before and after 3 and 6 months tamoxifen treated breast cancer patients. In addition, the changes in serum glycoproteins viz., hexose, hexosamine, and sialic acid and lysosomal enzymes such as N-acetyl-beta-D-glucosaminidase, beta-D-galactosidase, and beta-D-glucuronidase were analysed in these patients. These values were compared with their age matched healthy control subjects. At 6 months evaluation, the tamoxifen treated postmenopausal breast cancer women showed a statistically significant decreased (p 〈 0.001, 0.05 respectively) levels of LDH, SGOT, SGPT, alkaline and acid phosphatases than their baseline values. Similarly, the levels of hexose, hexosamine, and sialic acid and N-acetyl-beta-D-glucosaminidase, beta-D-galactosidase, and beta-D-glucuronidase were decreased significantly (p 〈 0.001 ) in tamoxifen received postmenopausal women. The result of this study suggested that tamoxifen potentially retard the metastasis of breast cancer as well as the bone demineralisation in postmenopausal breast cancer women. Thus, tamoxifen may also have its antitumour activity through its beneficial effects on tumour marker enzymes and serum proteins in breast cancer women.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006874005764
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  • 35
    Electronic Resource
    Electronic Resource
    Induction of programmed cell death in human retinoblastoma Y79 cells by C2-ceramide (1998)
    Springer
    Molecular and cellular biochemistry 185 (1998), S. 7-15 
    Details
    ISSN: 1573-4919
    Keywords: human retinoblastoma cells ; apoptosis ; ceramide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract C2-ceramide, a cell-permeable analogue of ceramide, induced significant, dose- and time-dependent death in human retinoblastoma Y79 cells. Dying cells strongly displayed the morphology of apoptosis as characterized by microscopic evidence of cell shrinkage, membrane blebbing, nuclear and chromatin condensation and degeneration of the nucleus into membrane-bound apoptotic bodies. Upon induction of apoptosis Y79 cells evidence early phosphatidylserine externalization, as shown by annexin V-FITC. Apoptosis was also assessed by monitoring changes in cell granularity by staining with the combined fluorescent dyes acridine orange and ethidium bromide. C2-ceramide induced these morphological changes without a concomitant production of oligonucleosomal fragments responsible for the DNA ladder and without changes in p53 protein level. Apoptosis was accompanied by accumulation of a modified Bcl-2 protein with a slower-mobility form, and by proteolytic cleavage of PARP. The effect seemed to be specific for C2-ceramide, as C2-dihydroceramide, or other amphiphilic lipid analogues, or products of ceramide hydrolysis were ineffective. The effect also depended on mRNA and protein synthesis as it was markedly inhibited by actinomycin D and cycloheximide. Sphingomyelinase and interleukin-lβ, which are known to activate the sphingomyelin turnover leading to ceramide generation, also induced apoptosis mimicking the effects of ceramide. These findings propose ceramide as an activator of the suicidal program in Y79 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006836428202
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  • 36
    Electronic Resource
    Electronic Resource
    Estrogen activates raf-1 kinase and induces expression of Egr-1 in MCF-7 breast cancer cells (1998)
    Springer
    Molecular and cellular biochemistry 189 (1998), S. 119-125 
    Details
    ISSN: 1573-4919
    Keywords: estrogen ; breast cancer ; raf-1 kinase ; early growth response gene-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract We have investigated whether the raf-1 kinase, a downstream mediator of both receptor tyrosine kinase and protein kinase C signalling, is activated by estrogen (E2) in an estrogen receptor positive human breast cancer cell line. Autophosphorylation of raf-1 kinase was studied after treatment of MCF-7 cells with E2. E2-deprived cells contained low levels of raf-1 kinase activity. Treatment of cells for 1 min with E2 resulted in raf-1 autophosphorylation which was maximal within 5 min. Western blot analysis showed that raf-1 undergoes an electrophoretic mobility shift following E2 treatment. Egr-1 is a zinc finger-containing transcription factor which is expressed in association with raf-1 activation. Untreated MCF-7 cells expressed low levels of Egr-1 while E2 treatment resulted in an induction of egr-1 mRNA expression. These kinetics followed closely behind the E2 induction of c-myc mRNA. Egr-1 protein was similarly low in E2-deprived MCF-7 cells and was transiently increased following E2 treatment. Several studies have suggested that kinase activity may play a role in estrogen receptor (ER) activation. While activated v-raf failed to augment ER activation of transcription in transient transfection assays, a dominant negative mutant of raf-1 inhibited E2-induced transcription by 50% primarily as a result of increased baseline levels of E2 independent transcription. The results show that E2 can induce raf-1 kinase activity in MCF-7 breast cancer cells associated with the expression of an early growth response gene and modulation of ER signalling.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006827015320
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  • 37
    Electronic Resource
    Electronic Resource
    Ischemic preconditioning attenuates apoptotic cell death associated with ischemia/reperfusion (1998)
    Springer
    Molecular and cellular biochemistry 186 (1998), S. 139-145 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; DNA fragmentation ; ischemia/reperfusion ; ischemic preconditioning ; myocardial adaptation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Apoptosis or programmed cell death is a genetically controlled response for cells to commit suicide and is associated with DNA fragmentation or laddering. The common inducers of apoptosis include oxygen free radicals/oxidative stress and Ca2+ which are also implicated in the pathogenesis of myocardial ischemic reperfusion injury. To examine whether ischemic reperfusion injury is mediated by apoptotic cell death, isolated perfused rat hearts were subjected to 15, 30 or 60 min of ischemia as well as 15 min of ischemia followed by 30, 60, 90 or 120 min of reperfusion. At the end of each experiment, the heart was processed for the evaluation of apoptosis and DNA laddering. Apoptosis was studied by visualizing the apoptotic cardiomyocytes by direct fluorescence detection of digoxigenin-labeled genomic DNA using APOPTAG® in situ apoptosis detection kit. DNA laddering was evaluated by subjecting the DNA obtained from the hearts to 1.8% agarose gel electrophoresis and photographed under UV illumination. The results of our study revealed apoptotic cells only in the 90 and 120 min reperfused hearts as demonstrated by the intense fluorescence of the immunostained digoxigenin-labeled genomic DNA when observed under fluorescence microscopy. None of the ischemic hearts showed any evidence of apoptosis. These results were corroborated with the findings of DNA fragmentation which showed increased ladders of DNA bands in the same reperfused hearts representing integer multiples of the internucleosomal DNA length (about 180 bp). The presence of apoptotic cells and DNA fragmentation in the myocardium were completely abolished by subjecting the myocardium to repeated short-term ischemia and reperfusion which also reduced the ischemic reperfusion injury as evidenced by better recovery of left ventricular performance in the preconditioned myocardium. The results of this study indicate that reperfusion of ischemic heart, but not ischemia, induces apoptotic cell death and DNA fragmentation which can be inhibited by myocardial adaptation to ischemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006883717174
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  • 38
    Electronic Resource
    Electronic Resource
    Ouabain Induces Apoptosis on PHA-Activated Lymphocytes (1998)
    Springer
    Bioscience reports 18 (1998), S. 1-7 
    Details
    ISSN: 1573-4935
    Keywords: Ouabain ; apoptosis ; lymphocytes ; c-myc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Apoptotic cell death plays a critical role in immune system homeostasis, and c-myc protooncogene deregulated expression is a component of this programmed genomic response. Pharmacological intervention and modulation of peripheral lymphocytes apoptosis would have important implications. The present results indicate that ouabain, a specific inhibitor of Na+K+-ATPase, promotes an increased expression of c-myc mRNA, and induces apoptosis in PHA-stimulated lymphocytes. Furthermore, this ouabain-induced apoptosis cannot be counteracted by the addition of exogenous IL-2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022259832207
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  • 39
    Electronic Resource
    Electronic Resource
    Heat Shock Stress Induces Cleavage and Activation of PAK2 in Apoptotic Cells (1998)
    Springer
    The protein journal 17 (1998), S. 485-494 
    Details
    ISSN: 1573-4943
    Keywords: Heat shock ; apoptosis ; PAK2 ; caspase-3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Heat shock induces a stress response in mammalian cells and can also lead to apoptotic cell death. Here we report that a 36-kDa myelin basic protein (MBP) kinase detected by an in-gel kinase assay can be drastically activated in several cell types by heat shock. Immunoblot analysis revealed that this 36-kDa MBP kinase can be recognized by an antibody against the C-terminal region of a family of p21Cdc42/Rac-activated kinases (PAKs). By using this antibody and a PAK2-specific antibody against the N-terminal region of PAK2 as tools, we further demonstrated that heat shock can induce cleavage of PAK2 to generate a 36-kDa C-terminal catalytic fragment in mouse Balb/c 3T3 and human Hep 3B cells. The kinetic profile of appearance of the 36-kDa C-terminal catalytic fragment of PAK2 matched exactly with the activation of the 36-kDa MBP kinase in these cells induced by heat shock. In addition, the heat shock-induced cleavage and activation of PAK2 was found to be closely associated with both DNA fragmentation and activation of an ICE/CED-3 family cysteine protease termed caspase-3 in heat shock-treated Hep 3B cells. Moreover, blockage of the activation of caspase-3 by pretreating the cells with two specific tetrapeptidic inhibitors of caspases (Ac-DEVD-cho and Ac-YVAD-cmk) could substantially diminish the extent of heat shock-induced cleavage/activation of PAK2. Overall, our results point out that PAK2 is cleaved and activated during the heat shock-induced apoptotic cell death process and suggest that caspase-3 is involved in this process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022578820147
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  • 40
    Electronic Resource
    Electronic Resource
    New insights into the kinetic resistance to anticancer agents (1998)
    Springer
    Cytotechnology 27 (1998), S. 225-235 
    Details
    ISSN: 1573-0778
    Keywords: anticancer drugs ; apoptosis ; cell cycle ; drug resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Kinetic resistance plays a major role in the failure of chemotherapy towards many solid tumors. Kinetic resistance to cytotoxic drugs can be reproduced in vitro by growing the cells as multicellular spheroids (Multicellular Resistance) or as hyperconfluent cultures (Confluence-Dependent Resistance). Recent findings on the cell cycle regulation have permitted a better understanding why cancer cells which arrest in long quiescent phases are poorly sensitive to cell-cycle specific anticancer drugs. Two cyclin-dependent kinase inhibitors (CDKI) seem particularly involved in the cell cycle arrest at the G1 to S transition checkpoint: the p53-dependent p21cip1 protein which is activated by DNA damage and the p27kip1 which is a mediator of the contact inhibition signal. Cell quiescence could alter drug-induced apoptosis which is partly dependent on an active progression in the cell cycle and which is facilitated by overexpression of oncogenes such as c-Myc or cyclins. Investigations are yet necessary to determine the influence of the cell cycle on the balance between antagonizing (bcl-2, bcl-XL...) or stimulating (Bax, Bcl-XS, Fas...) factors in chemotherapy-induced apoptosis. Quiescent cells could also be protected from toxic agents by an enhanced expression of stress proteins, such as HSP27 which is induced by confluence. New strategies are required to circumvent kinetic resistance of solid tumors: adequate choice of anticancer agents whose activity is not altered by quiescence (radiation, cisplatin), recruitment from G1 to S/G2 phases by cell pretreatment with alkylating drugs or attenuation of CDKI activity by specific inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008025124242
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  • 41
    Electronic Resource
    Electronic Resource
    Development and characterization of new immortalized human breast cell lines (1998)
    Springer
    Cytotechnology 26 (1998), S. 207-218 
    Details
    ISSN: 1573-0778
    Keywords: breast cancer ; breast cell lines ; drugscreen target ; immortalized cell lines ; serum-free medium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract New human breast cell lines were developed from metastatic breast cancer tissues and normal breast tissues. Primary cultures were initiated from cellular outgrowths of explanted tissues or from mechanically isolated cells in two serum-free media. Cell cultures derived from both cancer and normal tissues were immortalized with pRSV-T plasmid to generate permanent breast cell lines that exhibited an epithelial morphology. Cell lines generated in this study were characterized with respect to morphology, growth rate, karyotype, presence of specific genes, and the expression of epithelial and breast markers. The cell lines expressed the epithelial cell markers, cytokeratins 8 and 18, and retained the capacity to produce human milk fat globulin. They also express the BRCA-1, erbB2, and EGF receptor genes and possess the H-ras, K-ras, and p53 genes. Preliminary data showed that one of the new cancer cell lines was highly sensitive to the cytotoxic action of taxol. It is envisioned that the new breast cell lines will be useful as targets for identification of therapeutic agents against breast cancer and as models for carcinogenesis studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007953429252
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  • 42
    Electronic Resource
    Electronic Resource
    Regulation of caspase activation in apoptosis: implications for transformation and drug resistance (1998)
    Springer
    Cytotechnology 27 (1998), S. 309-320 
    Details
    ISSN: 1573-0778
    Keywords: apoptosis ; caspases ; cell death ; proteases ; proteolysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Recent developments in the apoptosis field have uncovered a family of cysteine proteases, the Caspases, that act as signalling components as well as effectors of the cell death machinery. Caspases are constitutively present as inactive precursors within most cells and undergo proteolytic processing in response to diverse death-inducing stimuli to initiate the death programme. Active caspases can process other caspases of the same type as well as process caspases further downstream in the pathway that ultimately leads to collapse of the cell. This cellular collapse is thought to occur as a consequence of caspase-mediated cleavage of a diverse array of cellular substrates. Regulation of entry into the death programme is controlled at a number of levels by members of the Bcl-2 family, as well as by other cell death regulatory proteins. Recent data has shed light upon the mechanism of action of these regulatory molecules and suggests that the point of caspase activation is a major checkpoint in the cell death programme. Because many transformed cell populations possess derangements in cell death-regulatory genes, such as bcl-2, such cells frequently exhibit elevated resistance to cytotoxic chemotherapy. Thus, a deeper understanding of how apoptosis is normally regulated has therapeutic implications for disease states where the normal controls on the cell death machinery have been subverted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008014215581
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  • 43
    Electronic Resource
    Electronic Resource
    Variable functions of bcl-2 in mediating bioreactor stress- induced apoptosis in hybridoma cells (1998)
    Springer
    Cytotechnology 28 (1998), S. 177-188 
    Details
    ISSN: 1573-0778
    Keywords: apoptosis ; bcl-2 ; cell death ; hybridoma ; osmolarity ; pH ; shear ; stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract It has been demonstrated that the cell lines used for production of biopharmaceuticals are highly susceptible to apoptosis, and that over-expression of the bcl-2 oncogene can protect cells from death. Stress associated with the deprivation of nutrients has been shown to be the main cause of apoptosis in culture. We have extended these studies by investigating the mechanism of cell death under conditions of sub-optimal pH, shear stress and hyperosmolarity, and the protective action of bcl-2 over-expression. At pH 6, there was no clear evidence of protection from cell death. However, at pH 8, the viability of the bcl-2 transfected cells was about 20% higher relative to the control cells. Cultivation of control cells in a flat bottomed bioreactor with a magnetic stirrer bar without a pivot ring resulted in exposure of the cells to a high attrition effect. As a result, cell growth was retarded and a high level of cell death by apoptosis was observed. Under the same conditions, the bcl-2 transfected cell line exhibited a nearly five fold increase in viable cell number. This finding indicates that under apoptosis-suppressed conditions, shear stress can stimulate cell growth. Batch cultivation of both control and bcl-2 transfected cells in 350 and 400 mOsm media resulted in suppression of cell growth, athough the effect was most marked in the control cell line. Adaptation of control cells to 400 mOsm proved to be impossible to achieve. However, the bcl-2 transfected cells exhibited resistance to the osmotic stress resulting in long term adaptation to a high salt environment. Specific productivity of bcl-2 transfected cells grown in high osmolarity medium was 100% higher than that produced by non- adapted bcl-2 transfected cells grown in normal osmolarity medium. These results demonstrate that bcl-2 has a beneficial effect on hybridoma cultivation under a wide range of culture stresses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008002319400
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  • 44
    Electronic Resource
    Electronic Resource
    Calcium Channel Blockers and the Risk of Cancer: A Preclinical Assessment (1998)
    Springer
    Cardiovascular drugs and therapy 12 (1998), S. 157-169 
    Details
    ISSN: 1573-7241
    Keywords: calcium channel blockers ; dihydropyridines ; carcinogenesis ; cell proliferation ; apoptosis ; tumor promotion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The preclinical evidence for a potential influence of calcium channel blockers (CCBs) on carcinogenesis is discussed in the light of a broad database from rodent carcinogenicity studies as well as literature data. In all bioassays performed in rats and mice on the dihydropyridine CCBs — nifedipine, nimodipine, nisoldipine, and nitrendipine — no evidence was found for a carcinogenic potential of these compounds. Calcium is an essential intracellular signal for cell proliferation and apoptosis. The crucial role of increased cell proliferation in all stages of carcinogenesis is well documented. Some indirect experimental evidence also points to a role of defective apoptosis in tumor promotion. CCBs uniformly inhibit cell proliferation, whereas the influence of CCBs on apoptosis is inconsistent, resulting in an inhibition or increase in apoptosis dependent on cell type. Accordingly, antitumorigenic effects of CCBs have been reported based on their antiproliferative action. A tumor-promoting effect of CCBs based on inhibition of apoptosis, however, remains purely speculative and, in fact, can be denied based on the results of in vivo bioassays. It is therefore concluded that there is no preclinical evidence that should give rise to concern over the carcinogenic potential of dihydropyridine-type CCBs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007727010076
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  • 45
    Electronic Resource
    Electronic Resource
    Molecular Analysis of Two Mammary Carcinoma Cell Lines at the Transcriptional Level as a Model System for Progression of Breast Cancer (1998)
    Springer
    Clinical & experimental metastasis 16 (1998), S. 129-139 
    Details
    ISSN: 1573-7276
    Keywords: breast cancer ; differential gene expression ; new mitochondrial transcript ; new receptor ; tumor progression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract As a model system for the identification of genes involved in the progression of human breast cancer, differential gene expression in cell lines MCF-7 and MCF-7ADR was investigated. The latter cell line is derived from the former. Cell line MCF-7 is estrogen receptor-positive, vimentin-negative and uninvasive in the Matrigel outgrowth assay and in the nude mouse, while MCF-7ADR is estrogen receptor-negative, hormone-resistant, vimentin-positive, invasive in the Matrigel outgrowth assay and in the nude mouse and resistant to adriamycin due to overexpression of glycoprotein gp170. We have shown that tumor progression in this model system is mediated by transcriptional regulation of mitochondria-related genes, proteases, transmembrane receptors and cell cycle-related gene proteins. Among the genes differentially regulated at the transcriptional level in the cell lines MCF-7 and MCP-7ADR are a new mitochondrial transcript, mitochondrial creatine kinase, matrix metalloproteinase-1, stromelysin-3, urokinase and its receptor, tissue factor, E-cadherin, epidermal growth factor receptor, transmembrane proteins Mat-8 and progression associated protein (PAP), cyclin E, cyclin-dependent kinase-2 and cell cycle inhibitory proteins p16, p21 and p27.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1021941203905
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  • 46
    Electronic Resource
    Electronic Resource
    Regulation of tissue-degrading factors and in vitro invasiveness in progression of breast cancer cells (1998)
    Springer
    Clinical & experimental metastasis 16 (1998), S. 205-215 
    Details
    ISSN: 1573-7276
    Keywords: breast cancer ; in vitro invasiveness ; metalloproteinase system ; urokinase system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hormone-independent growth and invasiveness represent phenotypic properties acquired during early progression of breast cancer. We compared human mammary adenocarcinoma cells, MCF-7, which are estrogen-dependent and poorly metastatic, with the estrogen-independent and highly metastatic subline, MCF7/LCC1, with regard to expression of tissue-degrading factors of the matrix metalloproteinase (MMP)-and urokinase (uPA)-dependent degradative pathways, as well as for their in vitro invasive properties. Both cell lines showed low constitutive mRNA expression of the MMP inhibitor TIMP-1. Baseline expression of TIMP-2 mRNA was also very low in MCF-7 cells, whereas the MCF7/LCC1 level was much higher (~10- fold). Furthermore, both cell lines revealed low constitutive capacity to migrate in an in vitro invasion assay. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM) induced the mRNAs for TIMP-1 as well as for MMP-1, MMP-9, the uPA receptor, and the uPA inhibitor PAI-1, am ongst which only the responses of MMP-9 and PAI-1 were cell-specific. The mRNA levels of MMP-9 and PAI-1 were ~10-fold and ~15-fold higher in MCF7/LCC1 cells compared to MCF-7 cells. The secretion of immuno-reactive PAI-1 was considerably elevated (. 20-fold) in TPA-treated MCF7/LCC1 cells, whereas the TPA-dependent level of 92-kDa MMP-9 was only ~2-fold higher in MCF7/LCC1 cells than in MCF-7 cells. In both cell lines treatment with TPA was associated with an increase (~10-fold) in in vitro migration, which in the MCF7/LCC1 cells was significantly attenuated by a reconstituted basement membrane extract (Matrigel). These data suggest that TPA-responsive in vitro invasive properties that are probably associ-ated with PAI-1 expression may co-vary with progression from hormone-dependent to -independent breast cancer. © Rapid Science 1998
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006584624061
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  • 47
    Electronic Resource
    Electronic Resource
    The Role of the Tumor Suppressor Gene p53 in Cardiomyocyte Apoptosis (1998)
    Springer
    Heart failure reviews 3 (1998), S. 45-61 
    Details
    ISSN: 1573-7322
    Keywords: p53 ; p21/WAF-1/cip1 ; hypoxia ; cardiomyocytes ; apoptosis ; Fas ; TNF
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The possibility that a significant fraction of cardiac myocyte loss in various disease states occurs through apoptosis has elicited considerable attention in recent years. Evidence from human studies as well as in vitro and animal models of disease has shown that cardiac myocyte apoptosis can be induced by a variety of stimuli and in a number of disease states, including hypoxia, ischemia–reperfusion, myocardial infarction, mechanical stretch, aortic constriction, and heart failure. Because adult cardiac myocytes are terminally differentiated cells, the effects of such loss can never be fully compensated. Interest in cardiomyocyte apoptosis has been fueled by the possibility that once the proximal and distal signals were defined that initiate this pathway of cell removal, it would be possible to develop stategies to selectively interfere with such signaling and prevent the loss of cardiac function. This article examines the evidence for possible proximal stimuli of apoptosis in the heart, including ligand-dependent activation of the membrane receptors for Fas ligand and tumor necrosis factor-α, and, in particular, activation of the tumor suppressor gene p53. It relates what is known about the mechanism by which these stimuli in other cells induce apoptosis and discusses possible strategies for inhibiting apoptosis in the heart.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009754530487
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  • 48
    Electronic Resource
    Electronic Resource
    DNA Fragmentation and HSP72 Gene Expression by Adenovirus-Mediated Gene Transfer in Postischemic Gerbil Hippocampus and Ventricle (1998)
    Springer
    Metabolic brain disease 13 (1998), S. 211-223 
    Details
    ISSN: 1573-7365
    Keywords: Gene transfer ; lacZ gene ; ischemia ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A replication defective adenoviral vector containing the E. coli lacZ gene (AdCMVnLacZ) was directly injected into right hippocampus and lateral ventricle immediately after 5 min of transient global ischemia in gerbils. The relations between the lacZ gene expression and DNA fragmentation or heat shock protein 72 (HSP72) immunoreactivity were examined up to 21 days post ischemia. The lacZ gene was transiently expressed at 1 day in the hippocampus except around the CA1 region, while a large number of the periventricular cells strongly expressed the lacZ gene from 8 h to 7 days. In CA1 layer terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) positive cells, which were present only adjacent to the needle track at 8 h to 1 day, became more extensive in the whole CA1 layer at 3 to 7 days. TUNEL-positive cells were also detected around the DG at 1 day, around the needle track at 8 h to 3 days, and in the choroid plexus cells at 7 days HSP72 staining was detected in the subiculum at 1 to 3 days, the dentate granule cells at 8 h to 1 day, and in the CA3 or CA4 pyramidal cells at 1 to 3 days. Some lacZ expressing cells were double-positive with HSP72 in DG, while the majority of those were distinguished from the TUNEL-positive cells. Pyramidal neurons were almost completely lost in the CA1 sector at 7days after the ischemia. The present study demonstrates the successful LacZ gene transfer into the hippocampus and ventricle of postischemic gerbil brain except in the vulnerable CA1 layer by adenoviral vector injection. However adenovirus-mediated gene transfer may induce indirect apoptotic cell death in the DG and ventricle, in addition to direct traumatic injury around the needle track.
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    URL: http://dx.doi.org/10.1023/A:1023224025407
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  • 49
    Electronic Resource
    Electronic Resource
    5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon (1998)
    Springer
    Journal of neuro-oncology 36 (1998), S. 219-229 
    Details
    ISSN: 1573-7373
    Keywords: glioma cell ; bacterial cytosine deaminase ; 5-fluorocytosine ; interferon ; apoptosis ; DNA damage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To explore the antitumor mechanism of bacterial cytosine deaminase plus 5-fluorocytosine (CD/5-FCyt) in combination with interferons (IFNs), glioma cells were transduced with recombinant retroviruses expressing CD. The transduced glioma cells become sensitive to the nontoxic prodrug 5-FCyt. Apoptosis, DNA damage, bystander effect, and inhibition of thymidylate synthase (TS) and DNA synthesis are associated with CD/5-FCyt-mediated glioma cell killing. Furthermore, IFNs enhance this effect by increasing DNA damage and further inhibiting TS activity. The bystander effect is mediated by the release of cytotoxic metabolites of 5-FCyt into the extracellular milieu triggering apoptosis and DNA damage. Our data indicate that the use of CD/5-FCyt in combination with IFNs may provide a more effective approach for the treatment of brain tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005883128175
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  • 50
    Electronic Resource
    Electronic Resource
    Chemosensitivity of human malignant glioma: modulation by p53 gene transfer (1998)
    Springer
    Journal of neuro-oncology 39 (1998), S. 19-32 
    Details
    ISSN: 1573-7373
    Keywords: tumor suppressor gene ; p53 ; chemoresistance ; gene therapy ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Loss of wild-type p53 activity is one of the most common molecular abnormalities in human cancers including malignant gliomas. The p53 status is also thought to modulate sensitivity to irradiation and chemotherapy. Here, we studied the effect of a p53 gene transfer on the chemosensitivity of three human glioma cell lines with different endogenous p53 status (LN-229, wild-type; LN-18, mutant; LN-308, deleted), using the murine temperature-sensitive p53 val135 mutant. Expression of mutant p53 enhanced proliferation of LN-308 cells but reduced proliferation in the other cell lines. Expression of wild-type p53 caused reversible growth arrest of all cell lines but failed to induce apoptosis. Growth arrest induced by wild-type p53 was associated with strong induction of p21 expression. Strong induction of BAX expression and loss of BCL-2 expression, which are associated with p53-dependent apoptosis rather than growth arrest, were not observed. Wild-type p53 failed to sensitize glioma cells to cytotoxic drugs including BCNU, cytarabine, doxorubicin, teniposide and vincristine. The combined effects of wild-type p53 gene transfer and drug treatment were less than additive rather than synergistic, suggesting that the intracellular cascades activated by p53 and chemotherapy are rebundant. Unexpectedly, forced expression of mutant p53 modulated drug sensitivity in that it enhanced the toxicity of some drugs but attenuated the effects of others. These effects may represent a dominant negative effect of mutant p53 in LN-229 cells which have wild-type p53 activity but must be considered a gain of function-type effect in the other two cell lines which have no wild-type p53 activity. Importantly, no clear-cut pattern emerged among the three cell lines studied. We conclude that somatic gene therapy based on the reintroduction of p53 will limit the proliferation of human malignant glioma cells but is unlikely to induce clinically relevant sensitization to chemotherapy in these tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005910323338
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    The Use of Two Immunosuppressive Drugs, Cyclosporin A and Tacrolimus, to Inhibit Virus Replication and Apoptosis in Cells Infected with Feline Immunodeficiency Virus (1998)
    Springer
    Veterinary research communications 22 (1998), S. 553-563 
    Details
    ISSN: 1573-7446
    Keywords: apoptosis ; cyclosporin A ; FIV ; FK506 ; viral proliferation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An in vitro model of acute and chronic infections with feline immunodeficiency virus (FIV) was used to examine the effect of two immunosuppressive agents, cyclosporin A (CsA) and tacrolimus (also known as FK506), on the inhibition of the replication of the virus and of apoptosis. Both drugs significantly suppressed virus production in a dose-dependent manner in acutely and chronically infected cells. The ability of FK506 to inhibit virus replication was much lower than that of CsA, and was accompanied by marked antiproliferative activity. Treatment of infected cells with either CsA or FK506 did not affect the rise of free intracellular Ca2+ but did protect the cells against apoptosis. Thus, the antiviral activity of CsA and FK506 makes these compounds promising candidates for the development of drugs suitable for the treatment of AIDS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006197804888
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  • 52
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    Soluble CD95 (Fas/APO-1) in Malignant Glioma: (No) Implications for CD95-based Immunotherapy? (1998)
    Springer
    Journal of neuro-oncology 40 (1998), S. 233-235 
    Details
    ISSN: 1573-7373
    Keywords: CD95 ; glioma ; apoptosis ; CSF ; brain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract CD95 targeting is a novel approach of immunotherapy for malignant glioma that might be antagonized by the release of soluble CD95 by the tumor cells. An alternatively spliced CD95 mRNA that encodes a secreted CD95 variant has been detected in glioma cell lines in vitro and in human tumors in vivo. Here, we report that the levels of soluble CD95 in the serum of malignant glioma patients do not differ from those of lumbar disk disease patients. Soluble CD95 was detected in the CSF in 2 of 20 malignant glioma patients by ELISA. Bioassay studies indicate that these low levels of soluble CD95 in the CSF of some patients with malignant glioma cells are unlikely to interfere with CD95-based immunotherapy of malignant gliomas in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006173019048
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  • 53
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    Pharmacological Enhancement of Radiosurgery Response: Studies on an in Vitro Model System (1998)
    Springer
    Journal of radiosurgery 1 (1998), S. 51-56 
    Details
    ISSN: 1573-8752
    Keywords: Gamma knife ; apoptosis ; antiestrogen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Gamma-knife radiosurgery is one of the only means of treating otherwise inoperable intracranial neoplasia. At present the mechanism by which single-dose γ-radiation reduces tumor bulk is unknown. Using the human mammary cell line MCF-7 to represent a metastatic tumor often treated by γ-knife radiosurgery, we show here that γ-radiation provided by the γ knife dose dependency reduced growth and a component of this response was the induction of apoptotic cell death. Since we have shown previously that, for estrogen receptor-containing pituitary tumor cells, the pure antiestrogen, ZM 182780, modulates cell survival, further experiments were performed in which γ-irradiation was combined with ZM 182780 or the more familiar antiestrogen, tamoxifen. Our data demonstrate that although tamoxifen was as effective as ZM 182780 at blocking the transcriptional activity of the estrogen receptor, it was the pure antiestrogen that significantly enhanced apoptosis induced by γ-irradiation. These results on combining γ-irradiation with a pure antiestrogen offer a new therapeutic paradigm by which the effectiveness of γ-knife treatment could be enhanced by agents that modulate the apoptotic pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/B:JORA.0000010877.65003.31
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  • 54
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    Breast cancer in Australian women under the age of 40 (1998)
    Springer
    Cancer causes & control 9 (1998), S. 189-198 
    Details
    ISSN: 1573-7225
    Keywords: Age of onset ; Australia ; breast cancer ; family history ; height ; oral contraceptives ; parity ; weight
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives: A case-control-family study of breast cancer in women under the age of 40 was carried out in Melbourne and Sydney, Australia, from 1992 to 1995 to determine the risk factors for these women. Subjects included 467 incident cases identified by state cancer registries and 408 population-based controls. Methods: All participants completed a structured risk-factor questionnaire and family pedigree during an in-person interview. Where possible, cancers in first- and second-degree relatives were verified. Results: Multiple logistic regression analysis showed that the strongest risk factor for breast cancer was a family history of the disease - having at least one affected first-degree relative trebled the risk (relative risk [RR] = 3.3, 95 percent confidence interval [CI] = 1.9-5.8). Risk increased with height by three percent (standard error [SE] of one percent) per cm, and after adjusting for height, there was evidence for a decreased risk in women weighing 73 kg or more. There was an increased risk of breast cancer after the first full-term birth (RR = 1.8, CI = 1.0-3.5) but this risk fell by 30 percent (SE = 11 percent) with each subsequent livebirth. Conclusions: The effects of other reproductive factors and oral contraceptive use, although not nominally significant, were in accord with published findings from similar studies in young women. This study of Australian women has indicated that some risk factors for breast cancer in women under age 40 differ from those reported for older women either in direction (e.g., weight) or relative importance (e.g., family history).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008886328352
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    Physical activity and breast cancer risk in the College Alumni Health Study (United States) (1998)
    Springer
    Cancer causes & control 9 (1998), S. 433-439 
    Details
    ISSN: 1573-7225
    Keywords: Body mass ; breast cancer ; menopause ; physical activity ; United States ; women
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives: It is unclear whether physical activity is associated with a reduced risk of breast cancer. Some studies also suggest different effects between pre- and postmenopausal women, and lean and heavy women. Methods: We followed 1,566 University of Pennsylvania alumnae (mean age, 45.5 years), initially free of breast cancer, from 1962 until 1993. Physical activity at baseline was assessed by asking women about stairs climbed, blocks walked, and sports played. We estimated energy expenditure and categorized women into approximate thirds (〈 500, 500-999, 1,000+ kcal/wk). We identified 109 breast cancer cases during 35,365 person-years from follow-up questionnaires or from death certificates. Results: After adjustment for age and body mass index (BMI) (kg/m2), the relative risk (RR) of breast cancer was 0.92 (95 percent confidence interval [CI]=0.58-1.45) among women expending 500-999 kcal/wk and 0.73 (CI=0.46-1.14) for those expending 1,000+ kcal/wk, compared with women expending 〈 500 kcal/wk (P trend=0.17). This association was modified by menopausal status, but not BMI. For postmenopausal women, corresponding RRs were 0.95 (CI=0.58-1.57) and 0.49 (CI=0.28-0.86), respectively (P trend=0.015). Increased physical activity in premenopausal women was not significantly associated with decreased risk of breast cancer. Conclusions: These data support an inverse association between physical activity and breast cancer among postmenopausal women. Cancer Causes and Control 1998, 9, 433–439
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008827903302
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    Molecular Regulation of Cell Death and Therapeutic Strategies for Cell Death Induction in Prostate Carcinoma (1998)
    Springer
    Cancer and metastasis reviews 17 (1998), S. 345-351 
    Details
    ISSN: 1573-7233
    Keywords: prostate cancer ; apoptosis ; bcl-2 ; bax ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Many of the common molecular alterations associated with prostate cancer progression involve genes known to regulate cell death susceptibility. The significance of these molecular events is discussed in the context of developing and implementing new strategies designed to restore cell death susceptibility in prostate cancer cells and overcome therapeutic resistance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006170332301
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  • 57
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    Tumor Necrosis Factor-Induced Cytotoxicity is Not Related to Rates of Mitochondrial Morphological Abnormalities or Autophagy-Changes that can be Mediated by TNFR-I or TNFR-II (1998)
    Springer
    Bioscience reports 18 (1998), S. 329-340 
    Details
    ISSN: 1573-4935
    Keywords: Tumor necrosis factor ; mitochondria ; autophagy ; apoptosis ; necrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Tumor necrosis factor (TNF) may cause apoptosis or necrosis and induces mitochondrial changes that have been proposed to be central to cytotoxicity. We report similar patterns of TNF-induced mitochondrial morphological alterations and autophagy in cell types with differing sensitivity to TNF-induced cytotoxicity. Specific ligation of TNFR-I or TNFR-II induces different rates of apoptosis and mitochondrial morphological change, but similar rates of autophagy. These changes do not invariably lead to cell death, and survival or progression to apoptosis or necrosis following TNF exposure may depend in part on the extent of mitochondrial damage and/or the autophagic capacity of the cell.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020261316486
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  • 58
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    The anti-cancer drug etoposide can induce caspase-8 processing and apoptosis in the absence of CD95 receptor-ligand interaction (1998)
    Springer
    Apoptosis 3 (1998), S. 17-25 
    Details
    ISSN: 1573-675X
    Keywords: Anti-cancer drug ; apoptosis ; CD95 (APO-1/Fas) ; DNA damage ; etoposide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Caspase-8 (FLICE) can associate with and be activated by CD95 (APO-1/Fas), an apoptosis-inducing member of the Tumour Necrosis Factor receptor family. We find that, in Jurkat T cells, the DNA damaging anti-cancer drug etoposide induces apoptosis and, surprisingly, processing of caspase-8. Therefore, we have investigated whether etoposide involves CD95 receptor activation. We find that etoposide does not induce CD95 ligand expression at the mRNA level. In addition, blocking of CD95 receptor function with a specific antibody does not inhibit etoposide-induced apoptosis. Apparently, in Jurkat cells, etoposide can induce caspase-8 processing and apoptosis in a CD95-independent fashion. Likewise, we find that thymocytes from the CD95-deficient lpr/lpr mouse strain readily undergo apoptosis in response to etoposide. Moreover, since inhibition of the secretory pathway with brefeldin A does not inhibit etoposide-induced apoptosis, we exclude the requirement for a newly synthesizedreceptor ligand to induce the apoptotic pathway. We conclude that, at least in certain cell types, etoposide does not require CD95 receptor function to induce caspase-8 processing and apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009603001888
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  • 59
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    Early Features of Apoptosis Detected by Four Different Flow Cytometry Assays (1998)
    Springer
    Apoptosis 3 (1998), S. 115-121 
    Details
    ISSN: 1573-675X
    Keywords: 7A6-antigen ; Annexin V ; apoptosis ; DNA fragmentation ; phosphatidyl serine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The objective of this study was to investigate the sensitivity, specificity and reproducibility of some frequently used apoptosis assays. The degree of apoptosis was tested in two T-lymphoblastoid cell lines, HSB and Jurkat, in which apoptosis was induced by ionizing radiation. HSB and Jurkat samples were taken before, and 0, 2, 4, 6, 8 and 24 h after irradiation with 6 and 10 Gray, or with 10 and 14 Gray, respectively. Four frequently used flow cytometric techniques were evaluated: (i) Annexin V/Propidium Iodide assay, detecting the translocation of phosphatidylserine to the outer leaflet of the plasma membrane, simultaneously with preservation of the membrane integrity; (ii) Terminal deoxynucleotidyl Transferase (TdT) Uridine triphosphate (UTP) nick end labelling (TUNEL), revealing the presence of DNA strand breaks; (iii) DNA-flow cytometry, measuring DNA-stainability (DNA-fragmentation assay) and (iv) Phycoerythrin-labelled (PE) Apo2.7-assay, a monoclonal antibody against 7A6 antigen, a protein, which becomes exposed upon the mitochondrial membrane during apoptosis. As a general standard for identifying that apoptosis had occurred, the cells were assessed for the presence of DNA-laddering on agar gel electrophoresis and by demonstration of characteristic cell morphology. Results were as follows: Fluorescein Isothiocyanate (FITC)-labelled Annexin V/Propidium iodide flow cytometry appeared to be the most sensitive, the most specific and the most user-friendly test for measurement of apoptosis of cells in culture conditions in suspension. The expression of 7A6 antigen on the mitochondrial membrane appeared to be not specific for apoptotic cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009649025439
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  • 60
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    α1-Antichymotrypsin inhibits chymotrypsin-induced apoptosis in rat hepatoma cells (1998)
    Springer
    Apoptosis 3 (1998), S. 155-160 
    Details
    ISSN: 1573-675X
    Keywords: α-1 antichymotrypsin ; apoptosis ; chymotrypsin ; DNA fragmentation ; hepatoma cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Increased serum levels of α1-antichymotrypsin (α1ACT) are observed in some cancer patients, especially those with hepatocellular carcinoma. A possible role of α1ACT in tumour growth has been suggested, but this remains uncertain. We have demonstrated that α1ACT inhibited chymotrypsin-induced apoptosis in rat hepatoma H4 cells. Even low concentrations of chymotrypsin (but not trypsin) induce apoptosis in H4 cells with a minimum effective concentration of 2.4 × 10−2 units/ml (0.5 μg/ml), and this apoptosis was inhibited by α1ACT in a concentration-dependent manner. Furthermore, the concentrations of α1ACT required to inhibit the apoptosis were lower than normal serum levels. These results may indicate that α1ACT plays a role in the apoptosis of rat hepatoma cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009694621397
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  • 61
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    Calcium Dobesilate protects human peripheral blood mononuclear cells from oxidation and apoptosis (1998)
    Springer
    Apoptosis 3 (1998), S. 41-49 
    Details
    ISSN: 1573-675X
    Keywords: Acivicin ; antioxidants ; apoptosis ; Calcium Dobesilate ; Doxium ® ; deoxyribose ; γ-glutamyltransferase ; glutathione ; glutathione S-transferase ; human peripheral blood mononuclear cells ; lipid peroxidation ; membrane permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The antioxidant effects of Calcium Dobesilate (CD, Doxium ®) were investigated in relation to the oxidative status, apoptosis and in vitro proliferation of human peripheral blood mononuclear cells (PBMC) isolated from healthy donors. CD alone did not modify cell growth in vitrountil 10 μM. This molecule counteracted oxidative damages generated by the high reducing sugar dR and was shown to reduce apoptosis by delaying both membrane permeability changes and DNA fragmentation. CD 10 μM affected in a time-dependent dynamics several parameters representative of the cellular oxidative status. In particular, CD significantly increased the activity of glutathione S-transferase (GST) after three days of treatment and also, but to a lower extent, the activity of γ-glutamyltransferase (γ-GT). Both enzymes are known to be involved in the glutathione (GSH) metabolic cycle. This enzymatic behaviour was reversed at seven days of treatment, with a significant GST decrease and a γ-GT activation. After seven days of CD exposure, the intracellular GSH content was enhanced and this resulted in a dramatic decrease in lipid peroxidation, underlining the powerful antioxidant properties of CD in human PBMC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009659119635
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  • 62
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    Increased numbers of alveolar macrophages with apoptotic bodies predict lung carcinoma (1998)
    Springer
    Apoptosis 3 (1998), S. 261-266 
    Details
    ISSN: 1573-675X
    Keywords: Alveolar macrophages ; apoptosis ; apoptotic bodies ; lung carcinoma ; sputum smear
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract In our previous study on fixed tissue blocks, we reported a high apoptotic rate in patients with operated small cell lung carcinomas. In addition to tumour cells, numerous apoptotic bodies could also be found within alveolar macrophages within and close to tumour tissue. In order to test if such cells could be found in sputum smears and if their presence could be utilized as a marker in tumour diagnosis, we analyzed the occurrence of alveolar macrophages with apoptotic bodies (AMWABs) in a set of sputum smear and BAL samples from patients with and without a pulmonary malignancy. An increased amount of AMWABs in the cytoplasm could be found in sputum and BAL samples from patients with lung cancer. Interestingly, AMWABs could also be seen in patients with a histologically confirmed pulmonary malignancy, but with no detectable tumour cells in their sputum smear. Thus, the presence AMWABs in sputum smears could serve as a more sensitive marker of pulmonary malignancy than the prese nce of malignant cells per se. This is the first report describing apoptotic bodies in macrophages and the utility of their detection in cancer diagnosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009661209006
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  • 63
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    Heat-induced testicular apoptosis occurs independently of hormonal depletion (1998)
    Springer
    Apoptosis 3 (1998), S. 281-288 
    Details
    ISSN: 1573-675X
    Keywords: Androgen ; apoptosis ; heat stress ; hormone ; temperature ; testis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Previous studies have demonstrated that testicular germ cell apoptosis can be induced both by heat stress and by withdrawal of androgens and gonadotrophins. To investigate whether heat-induced germ cell apoptosis occurs independently of the altered levels of hormones that occur with heat exposure, mouse testicular apoptosis was studied using an in vitro system with controlled levels of testosterone, FSH and LH. It was observed that cells underwent apoptosis sooner in the absence of hormones at the same temperature. Apoptosis also occurred earlier at abdominal temperature compared to scrotal temperature with the same hormonal levels. No somatic tissues studied underwent apoptosis at 37°C under the same culture conditions. These results suggest that heat stress may independently activate an apoptotic pathway in the testis, and that hormone deprivation may induce apoptosis via a separate mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009665309915
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  • 64
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    Bcl-2 Antisense Therapy for Cancer: The Art of Persuading Tumour Cells to Commit Suicide (1998)
    Springer
    Apoptosis 3 (1998), S. 67-74 
    Details
    ISSN: 1573-675X
    Keywords: Antisense therapeutics ; apoptosis ; Bcl-2 ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The Bcl-2 oncoprotein is a potent inhibitor of apoptosis induced by numerous physiological and pathological stimuli, and uncontrolled cell survival due to Bcl-2 overexpression has been shown to contribute to tumour formation and the development of autoimmune diseases. The multifunctional action of Bcl-2 is thought to prevent activation of the ced3/caspase-3 subfamily of ICE proteases, resulting in suppression of the death effector machinery. Since most conventional anti-cancer agents act by triggering this suicide pathway, overexpression of Bcl-2 in cancer cells has also been associated with drug resistance. The antisense approach to inhibition of gene expression relies on the binding of small synthetic oligodeoxynucleotides to a complementary base sequence on a target mRNA. As a consequence, expression of the corresponding gene is downregulated due to endonuclease-mediated hydrolysis of the mRNA strand, or to translational arrest arising from sterie hindrance by the RNA:DNA heterodimer. Since these mechanisms of action differ from those exerted by conventional anticancer agents, antisense oligodeoxynucleotides designed to specifically inhibit bcl-2 gene expression hold great promise as agents that could overcome clinical drug resistance, and improve the treatment outcome of many hitherto incurable cancer diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009636722713
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  • 65
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    Induction of apoptosis by gemcitabine in BG-1 human ovarian cancer cells compared with induction by staurosporine, paclitaxel and cisplatin (1998)
    Springer
    Apoptosis 3 (1998), S. 439-449 
    Details
    ISSN: 1573-675X
    Keywords: Annexin V ; apoptosis ; caspase ; gemcitabine ; ovarian cancer ; staurosporine.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A variety of chemotherapeutic agents induce cell death via apoptosis. We had shown previously that gemcitabine (2′,2′-difluorodeoxycytidine) induced an atypical apoptosis in BG-1 human ovarian cancer cells; therefore, further studies were conducted to characterize more precisely gemcitabine-induced apoptosis in BG-1 cells compared to a general inducer of apoptosis, staurosporine. BG-1 cells exposed to 0.5, 1.0 and 10 μM gemcitabine for 8 h, or staurosporine (1.0 μM) for 6 h, exhibited high molecular weight DNA fragmentation (50 kbp); however, only staurosporine treatment produced internucleosomal DNA fragments (200 bp) in a laddered pattern on the agarose gel. Staurosporine (1.0 μM) rapidly induced phosphatidylserine plasma membrane translocation that increased linearly with time as measured by annexin V-FITC binding, and similar kinetics were observed for caspase activation by staurosporine in BG-1 cells. In contrast, 10 μM gemcitabine increased phosphatidylserine expression in a small fraction of cells (5–10%) vs. untreated controls over the course of 48 h and significant caspase activity was detected within 12 h of drug exposure. Time-lapse video microscopy of BG-1 cells exposed to 1.0 μM staurosporine or 10 μM gemcitabine for up to 72 h showed that the morphologic changes and kinetics of cell death induced by these agents differed significantly. We also evaluated the apoptosis induced by paclitaxel (a mitotic poison) and cisplatin (an agent not dependent on cell cycle functions) in BG-1 cells by these methods because these drugs are used clinically to treat ovarian cancer. Our findings demonstrate that the kinetics of apoptotic cell death induced by gemcitabine and other chemotherapeutic agents should be taken into account when designing treatment strategies for ovarian cancer.
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    URL: http://dx.doi.org/10.1023/A:1009614703977
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  • 66
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    Induction of apoptosis in proliferating lymphocytes by tricyclic antidepressants (1998)
    Springer
    Apoptosis 3 (1998), S. 255-260 
    Details
    ISSN: 1573-675X
    Keywords: Antidepressants ; apoptosis ; induction ; lymphoblasts ; lymphocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We have previously found that tricyclic antidepressants (TCAs) induce apoptosis in quiescent human lymphocytes. The aim of the present study was to evaluate if TCAs induce apoptosis in proliferating human lymphocytes and in established blastoid lymphocytes also. The development of conA-induced lymphoblast populations was followed by measuring the CD25 membrane expression. Three TCA compounds were run with the following concentrations: imipramine (10, 20, 30, 40, 60μ M), clomipramine (1, 10, 20, 30, 40μ M) and citalopram (40, 60, 80, 100, 180μ M). They all induced a dose-dependent apoptosis both in continuously transformed, as well as in established lymphoblasts. Preincubation of the TCA up to 48 h did not significantly increase induction of apoptosis. The three drugs tested were found to be potent inducers of apoptosis in proliferating lymphocytes. Furthermore, we found that the apoptotic populations in proliferating and in established blastoid lymphocytes were of f airly the same magnitude than in the corresponding population in TCA-incubated resting lymphocytes. In conclusion, we demonstrate that TCAs induce apoptosis in proliferating lymphocytes, as they do in quiescent lymphocytes. Furthermore, the exent of apoptosis was even more pronounced in TCA-incubated lymphoblasts compared to TCA-treated resting lymphocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009609224936
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  • 67
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    Apoptosis in non-proliferating cells: implications for viral infection and tumourigenesis (1998)
    Springer
    Apoptosis 3 (1998), S. 381-385 
    Details
    ISSN: 1573-675X
    Keywords: AIDS ; apoptosis ; cell cycle ; cell quiescence ; HIV-1 infection ; tumourigenesis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract To date much attention has been focused on regulation of apoptosis in proliferating cells. However, recent evidence shows that regulation of apoptosis in quiescent tissue plays an important role in homeostasis of the organism. This review examines the implications of apoptosis of quiescent cells for both tumourigenesis and viral infection such as HIV. In this article we propose a dual role for cellular activation in the homeostasis regulation. In this model cellular mitogens not only activate quiescent cells into the active cell cycle, but under certain conditions, loss of quiescence may result in apoptosis. The loss of quiescence-associated apoptosis may play a significant role in tumourigenesis and viral infections.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009693517181
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    Caspases in ischaemic brain injury and neurodegenerative disease (1998)
    Springer
    Apoptosis 3 (1998), S. 387-394 
    Details
    ISSN: 1573-675X
    Keywords: Alzheimer's disease ; apoptosis ; hypoxia-ischaemia ; neuronal death ; programmed cell death ; stroke.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The importance of caspases in developmental neuronal death is well-established. Recent data provide compelling evidence of caspase activation after ischaemic brain injury. Caspase inhibitors reduce cell death in several models of ischaemic injury. This review summarizes our current understanding of caspase function in ischaemic brain injury and examines the accumulating evidence of caspase participation in several neurodegenerative diseases. The therapeutic consequences of caspase inhibitor treatment in reducing cell death after such injury are also discussed.
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    URL: http://dx.doi.org/10.1023/A:1009602401251
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    Dipropylcyclopentylxanthine triggers apoptosis in cells from patients with myeloid leukaemia (1998)
    Springer
    Apoptosis 3 (1998), S. 183-193 
    Details
    ISSN: 1573-675X
    Keywords: 1,3-Dipropyl-8-cyclopentylxanthine ; apoptosis ; blood cells ; leukaemia therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a xanthine analogue used as a selective antagonist of adenosine receptors, caused apoptosis in a variety of leukaemia-derived cell lines as well as in cells from patients with myeloid leukaemia. Apoptosis was assessed by flow cytometry, by DNA fragmentation and by accumulation of histones, H2A, H2B, R3 and H4, in the nucleoplasm of cells. Cell cycle analysis indicated that apoptosis occurred irrespective of the cell cycle phase. DPCPX did not trigger apoptosis in resting human peripheral blood lymphocytes; neither did it potentiate the apoptotic effect of phytohemagglutinin (PHA), when these cells were activated by PHA. These results indicate that DPCPX may be useful in the therapy of proliferative disorders of the hematopoietic system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009650906376
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  • 70
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    Crocidolite asbestos causes an induction of p53 and apoptosis in cultured A-549 lung carcinoma cells (1998)
    Springer
    Apoptosis 3 (1998), S. 203-212 
    Details
    ISSN: 1573-675X
    Keywords: A-549 lung carcinoma cells ; apoptosis ; crocidolite ; in situ 3′-end labelling ; p53 response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A number of genotoxic chemicals and agents, such as benzo(a)pyrene and ultraviolet light, are able to induce nuclear accumulation of p53 protein. Usually, this response is transient and a consequence of stabilization of the wild-type p53 protein. After withdrawal of the exposure, the amount of p53 protein returns to a normal level within hours or a few days. We have studied the p53 response to the exposure of crocidolite asbestos in A-549 lung carcinoma cells using three different methods, i.e., p53 immunohistochemistry, Western blotting and metabolic labelling followed by p53 immunoprecipitation. With these techniques we demonstrate a dose-dependent p53 nuclear response to crocidolite exposure. The half-life of p53 protein in A-549 lung carcinoma cells cultured in serum-free media increased from 30 up to 80 min, and the protein reacted with a wild-type specific antibody suggesting that it was in a wild-type conformation. In situ 3′-end labelling of A-549 cells demonstrated a dose-dependent increase in apoptotic activity. Our data support the idea that increased apoptotic activity, induced by crocidolite, is mediated by p53.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009655007284
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  • 71
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    The time course of nerve growth factor content in different neuropsychiatric diseases – a unifying hypothesis (1998)
    Springer
    Journal of neural transmission 105 (1998), S. 871-903 
    Details
    ISSN: 1435-1463
    Keywords: Keywords: Alzheimer's disease ; apoptosis ; cytokine ; diabetes ; alcohol ; nerve growth factor (NGF) ; neurodegeneration ; neuropathy ; neuroplasticity ; neurotrophin ; p75 ; trkA.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Nerve growth factor (NGF) is the prototype of related neurotrophic proteins, the so-called neurotrophins. NGF is essential for proper development of sympathetic and neural crest-derived sensory neurons of the peripheral nervous system (PNS) as well as of the neurons in the cholinergic basal forebrain (CBF). In the mature peripheral and central nervous system (CNS) NGF is also biologically active; NGF facilitates neuronal plasticity and regulates synaptic transmission and connectivity. Besides this well established neurotrophic function, recent findings suggest a role of NGF in neuroimmune and stress-associated processes, which NGF imparts not only as the classical "target-derived messenger", that is retrogradly transported within NGF-sensitive neurons, but also as para- and autocrine cytokine modulating the function of non-neuronal cells.. Since neurotrophins are produced in very small amounts in vivo, NGF-sensitive cells have to compete for the limited NGF even under physiological conditions, so that normally only less than 10% of NGF receptors (NGFR) are saturated with their endogenous ligand. Consequently, it is feasable that minute changes in NGF concentrations can influence neuronal function in an extensive way. Hence, one plausible pathomechanism of disease(s) may be that a deficiency in NGF leads to malfunction of NGF-sensitive neurons. The change in NGF concentrations in the course of several diseases, namely during alcoholic and diabetic neuropathy as well as in Alzheimer's disease (AD) and several lesion-models of the CBF, indicates that fluctuations of endogenous NGF concentrations in PNS and CNS follow a distinctive pattern. An initial deficit of NGF at the onset of pathological processes is typically followed by its temporary elevation, during which some neuronal deficits may be partially ameliorated. However, if the disease progresses a decrease of NGF is typically observed, which appears to be a "normalization" of formerly elevated NGF concentrations. In our hypothesis we postulate that after acute or chronic injuries NGF is up-regulated as an intrinsic attempt to regenerate NGF-sensitive neurons. After long-term exposure to noxious processes, however, this compensatory increase of NGF cannot be maintained and eventually breaks down. The extent of such a compensatory up-regulation may depend on age and condition of NGF-sensitive neurons as well as on the type of lesion (acute or chronic). Furthermore, we also postulate that an exceeding level of NGF or its chronic elevation could even be detrimental to neuronal functioning under certain conditions.. Thus, endogenous NGF has the capacity to modulate and even to compensate different kinds of harmful processes and in this way it may reinstate the homeostatic equilibrium. In our view, it seems to be a more appropriate app-roach to regard NGF changes as independent of classical constructs of neuropsychiatric diseases. Perhaps our understanding of NGF may even model for a new approach to the aetiology of multifactorial neuropsychiatric disorders.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007020050100
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  • 72
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    Death of Cerebellar Granule Neurons Induced by Piperine Is Distinct from that Induced by Low Potassium Medium (1998)
    Springer
    Neurochemical research 23 (1998), S. 97-102 
    Details
    ISSN: 1573-6903
    Keywords: Piperine ; cerebellar granule neurons ; neuronal death ; low K+medium ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We compared neurotoxicity of piperine and low K+on cultured cerebellar granule neurons. As considered from lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide reduction, both piperine and shifting from high K+(25 mM) to low K+(5.4 mM) were cytotoxic to cerebellar granule neurons. Protein synthesis inhibitors, cycloheximide and anisomycin, and an endonuclease inhibitor, aurintricarboxylic acid, were protective against low K+-induced neuronal death whereas they were ineffective against that induced by piperine. D-α-tocopherol, trolox, and a spin trap 3,3,5,5-tetramethyl-l-pyrroline-l-oxide were protective against piperine neurotoxicity whereas they had no effect on that induced by low K+. These results suggest that piperine and low K+may exert neurotoxic effects on cerebellar granule neurons through different mechanisms. Death of cerebellar granule neurons induced by piperine may be mediated by non-apoptotic mechanisms and may involve membrane lipid peroxidation and/or free radical generation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022461706344
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  • 73
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    Expression of Cell Cycle-Related Genes During Neuronal Apoptosis: Is there a Distinct Pattern? (1998)
    Springer
    Neurochemical research 23 (1998), S. 767-777 
    Details
    ISSN: 1573-6903
    Keywords: Post-mitotic neurons ; oxidative-stress ; cell-cycle ; apoptosis ; cyclin B ; cdk5
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An emerging hypothesis considers the process of neuronal apoptosis as a consequence of unscheduled and unsynchronized induction of cell cycle mediators. Induction of several cell cycle genes precedes neuronal apoptosis and may be involved in determination of cell fate. We have now characterized changes in expression of cell cycle genes during apoptosis induced by oxidative stress in chick post-mitotic sympathetic neurons. Induction of cyclin B occurred prior to the commitment of neurons to both dopamine- and peroxide-triggered apoptosis. Both the neuronal death and the rise in cyclin B were inhibited by antioxidant treatment, suggesting a functional role for cyclin B induction during neuronal apoptosis. Induction of the cyclin dependent kinase CDK5 protein coincided with the time point when neurons were irreversibly committed to die. Expression of other cell cycle mediators such as cyclin D1 and the cyclin dependent kinases CDC2 and CDK2 was undetected and not induced by exposure to oxidative stress. Comparative analysis of the profile of cell cycle mediators induced during neuronal apoptosis of different neuronal cell populations revealed no distinct pattern of events. There are no cell cycle stage-specific mediators that are ultimately stimulated during neuronal apoptosis, suggesting that multiple pathways of re-activating the dormant cell-cycle, converge to determine entry into apoptosis. Nevertheless, the existence of some cell cycle mediators, that were not reported so far to be induced in post mitotic neurons during oxidative stress, substantiate them as part of the strong differentiating forces.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022415611545
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  • 74
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    Single-strand breaks, cell cycle arrest and apoptosis in HL-60 and LLCPK1 cells exposed to 1,2-dibromo-3-chloropropane (1998)
    Springer
    Cell biology and toxicology 14 (1998), S. 267-282 
    Details
    ISSN: 1573-6822
    Keywords: apoptosis ; cell cycle ; DBCP ; DNA-damage ; HL-60 cells ; human renal proximal tubular cells ; LLCPK1 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We investigated 1,2-dibromo-3-chloropropane (DBCP)-induced DNA damage, cell cycle alterations and cell death in two cell lines, the human leukemia HL-60 and the pig kidney LLCPK1, both of which are derived from potential target sites for DBCP-induced toxicity. DBCP (30–300 µmol/L) caused a concentration-dependent increase in the levels of DNA single-strand breaks in both cell lines as well as in cultured human renal proximal tubular cells. After extended DBCP exposure in LLCPK1 cells (100 µmol/L, 30 h), the level of DNA breaks returned almost to control values. Incubation for 48 h showed a clear reduction of growth with DBCP concentrations as low as 10 µmol/L. Flow cytometric analysis showed that DBCP (1–10 µmol/L) exposure for 24 h caused an accumulation of LLCPK1 cells in the G2/M-phase. In HL-60 cells the accumulation in G2/M-phase was less marked, and at higher concentrations the cells accumulated in S-phase. Flow cytometric studies of HL-60 and LLCPK1 cells exposed to 100–500 µmol/L DBCP showed increased number of apoptotic cells/bodies with a lower DNA content than that of the G1 cells. Microscopic studies revealed that there were increased numbers of cells with nuclear condensation and fragmentation, indicating that apoptosis was the dominant mode of death in these cell lines, following exposure to DBCP. The characteristic ladder pattern of apoptotic cells was observed when DNA from DBCP-treated HL-60 cells and LLCPK1 cells was electrophoresed in agarose. The finding that DBCP can cause an accumulation of cells in G2/M-phase and induce apoptosis in vitro may be of importance for the development of DBCP-induced toxicity in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007482924707
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  • 75
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    Electronic Resource
    Oxygen Toxicity Induces Apoptosis in Neuronal Cells (1998)
    Springer
    Cellular and molecular neurobiology 18 (1998), S. 649-666 
    Details
    ISSN: 1573-6830
    Keywords: oxygen toxicity ; apoptosis ; neuronal cells ; neurotrophic factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. A high oxygen atmosphere induced apoptosis in cultured neuronal cells including PC12 cells and rat embryonic cortical, hippocampal, and basal forebrain neurons associated with DNA fragmentation and nuclear condensation. 2. The sensitivity of CNS neurons to a high-oxygen atmosphere was the following order; cortex 〉 basal forebrain 〉 hippocampus. 3. Cycloheximide and actinomycin-D inhibited the apoptosis, indicating that it depends on new macromolecular synthesis. In contrast, cultured postnatal CNS neurons were resistant to oxidative stress. 4. Neurotrophic factors such as nerve growth factor (NGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) blocked the apoptosis induced by a high-oxygen atmosphere.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020633919115
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  • 76
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    Soluble CD44 v5 and v6 in serum of patients with breast cancer. Correlation with expression of CD44 v5 and v6 variants in primary tumors and location of distant metastasis (1998)
    Springer
    Breast cancer research and treatment 47 (1998), S. 29-40 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; CD44 transmembrane receptor variants ; soluble CD44 v5 and v6 ; CD44 v5 and v6 expression ; metastatic disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Primary breast cancers were shown to overexpress CD44 v5 and v6 at the plasma membrane. However, the clinical significance of this overexpression remains unclear. Overexpression of CD44 v5 and v6 in primary breast cancers was found to correlate with metastasis and poor prognosis by some investigators, yet this correlation could not be confirmed by others using different antibodies. In this study the influence of metastatic disease, the site of metastasis, and the amount of CD44 v5 and v6 expression in the primary tumor on serum levels of the soluble forms of CD44 v5 and v6 (sCD44 v5 and v6) in breast cancer patients was investigated. Soluble CD44 v5 and v6 serum levels were measured by enzyme linked immuno sorbent assay in a group of breast cancer patients who developed metastases in various organs and in another group of patients with single organ metastasis. For control, sCD44 v5 and v6 levels were measured in breast cancer patients who remained free of metastasis and in healthy blood donors. Expression of plasma membrane bound CD44 v5 and v6 in the primary tumors of the patients with metastasis in various organs was correlated to sCD44 v5 and v6 levels in serum. Furthermore the size of sCD44 v6 was analyzed by immunoblot using a monoclonal antibody directed against CD44 v6. When metastases were detected, sCD44 v5 and v6 serum levels were increased as compared to levels measured one month after tumor surgery in patients free of metastases (p = 0.0025 and p = 0.0004). Six of 19 and 6 of 20 patients had sCD44 v5 and v6 serum levels above a cut-off level of 85 and 275 ng/mL, respectively. In these cases expression of CD44 v5 and v6 in the primary cancers was also elevated. Low sCD44 v5 and v6 serum levels were associated with weak expression of CD44 v5 and v6 in the respective primary cancers. As shown by statistical analysis of sCD44 v5 and v6 levels in 57 patients with single organ metastases, elevated sCD44 v6 levels but not sCD44 v5 levels were associated with metastases in liver or bone (p = 0.0025). Immunoblot analysis of soluble CD44 proteins in serum revealed two CD44 v6 specific signals of approximately 120 and 170 kDa. Increased sCD44 v5 and v6 serum levels in patients with breast cancer were influenced by the amount of CD44 v5 and v6 expression in the primary tumor by the site of metastasis. Elevated sCD44 v6 serum levels were preferentially found in patients with metastases in liver or bone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005913514376
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  • 77
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    Establishment and characterization of a new mammary adenocarcinoma cell line derived from MMTV neu transgenic mice (1998)
    Springer
    Breast cancer research and treatment 47 (1998), S. 171-180 
    Details
    ISSN: 1573-7217
    Keywords: mammary adenocarcinoma cell line ; MG 1361 ; MMTV-neu transgenic mice ; breast cancer ; hormone responsiveness ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A new murine cell line, named MG1361, was established from mammary adenocarcinomas arising in a MMTV-neu transgenic mouse lineage where breast tumors develop in 100% of females, due to the over-expression of the activated rat neu oncogene in the mammary gland. The MG1361 cell line shows an epithelial-like morphology, has a poor plating efficiency, low clonogenic capacity, and a doubling time of 23.8 hours. Karyotype and flow cytometry analysis revealed a hypotetraploid number of chromosomes, whereas cell cycle analysis showed 31.2% of cells to be in the G1 phase, 21.4% in S and 47.4% in G2 + M. This cell line maintains a high level of neu expression in vitro. The MG1361 cell line was tumorigenic when inoculated in immunodeficient (nude) mice and the derived tumors showed the same histological features as the primary tumors from which they were isolated. MG1361 cells were positive for specific ER and PgR binding which was competed by tamoxifen, making this cell line useful for the evaluation of endocrine therapy. Moreover, they were sensitive to etoposide treatment, suggesting that they could be a model for the study of chemotherapy-induced apoptosis. As the tumors arising in MMTV-neu transgenic mice have many features in common with human mammary adenocarcinomas (Sacco et al., Gene Therapy 1995; 2: 493–497), this cell line can be utilized to perform basic studies on the role of the neu oncogene in the maintenance of the transformed phenotype, and to test novel protocols of therapeutic strategies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005988715285
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  • 78
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    The insulin-like growth factors and breast cancer — revisited (1998)
    Springer
    Breast cancer research and treatment 47 (1998), S. 197-199 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; insulin-like growth factor system ; IGF-I receptor ; IGF-II receptor ; binding proteins ; prognosis ; transformation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In 1992, a special issue of Breast Cancer Research and Treatment was devoted to the insulin-like growth factors and breast cancer. In that issue, identification of the key components of the IGF system was reviewed and their potential role in breast cancer growth was described. In this issue, we revisit the IGF system with particular attention to data that further supports their role in the growth regulation of breast cancer. Several new facets of the IGF system are described, and several laboratories have more clearly defined how each individual component of the IGF system may influence breast cancer biology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005938615798
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  • 79
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    Changes in hormone receptors and proliferation markers in tamoxifen treated breast cancer patients and the relationship with response (1998)
    Springer
    Breast cancer research and treatment 48 (1998), S. 11-20 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; tamoxifen ; estrogen receptor ; progesterone receptor ; Ki67 ; S-phase fraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aim: To determine the effects of tamoxifen on the levels of hormone receptors and proliferation markers in the early phase of treatment and the relationship of the changes with tumor response in patients with primary breast cancer. Methods: Twenty-one women with primary, operable breast carcinomas were treated with tamoxifen 20 mg daily. Fine needle aspiration (FNA) was used to obtain samples prior to the start and at 14 days and 8-weeks post-treatment. From these samples estrogen receptor (ER), progesterone receptor (PgR), and Ki67 levels were determined using immunocytochemistry and ploidy and S-phase fraction (SPF) using flow cytometry. Tumor response was measured clinically according to UICC criteria. Results: There were 12 responders (2 CR, 10 PR) and 9 non-responders (2 NC, 7 PD). Responders were more likely to be ER + (p=0.002), PgR + (p=0.006), and low SPF (p=0.06). At 14 days post-tamoxifen, the median decrease in Ki67 (% cells staining) for responders was − 4.8 and for non-responders − 0.15 (p=0.005). This decrease was seen predominantly in ER + tumours. The difference in SPF was not significant. A decrease in ER was seen in 3/15 patients all of whom were responders. A rise in PgR was seen in 7/17 patients and all but one were responders. Similar changes for ER and PgR were seen at 8-weeks post-tamoxifen, although the reductions in Ki67 and SPF at that time point were not related to response. Conclusion: We have observed a decrease in Ki67 and ER and a rise in PgR after 14 days of treatment with tamoxifen that was related to subsequent response. This is the first study in which an early decrease in a proliferation marker has been shown to relate to subsequent clinical response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005973529921
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  • 80
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    Prostate-specific antigen induction by a steroid hormone in T47D cells growing in SCID mice (1998)
    Springer
    Breast cancer research and treatment 48 (1998), S. 73-80 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; LNCaP ; PSA ; SCID mice ; steroid hormones ; T47D
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies revealed that prostate-specific antigen (PSA) is present in 〉 30% of human breast tumor cytosols. Survival analysis showed that patients with PSA-producing tumors have a reduced risk for relapse, suggesting PSA to be an independent favorable prognostic marker for a large subset of breast cancer patients. The present investigation established an in vivo model for the induction of PSA in human breast cancer tumors growing as xenografts in severe combined immunodeficient (SCID) mice. The human mammary cancer cell-line T47D was grown i.m. in female mice. When the tumor and leg diameter reached 10 mm, the mice were stimulated daily with norgestrel for either 5 or 7 days to produce PSA, and sacrificed on day 8. The prostate cancer cell-line LNCaP was grown in male mice and functioned as a positive control for PSA production. After T47D and LNCaP mice were sacrificed, a highly sensitive immunofluorometric assay was used to analyze the PSA concentration in the tumor, muscle, liver, and kidney cytosols. Norgestrel-stimulated T47D mice showed significantly more PSA in the tumors compared to tumors of the control mice. However, PSA levels in tumors of the stimulated mice were significantly lower than those in the LNCaP xenografts. No PSA levels above background were present in the blood and normal tissue of the norgestrel-stimulated or control T47D xenografts. This mouse model will be a valuable tool for investigating and screening new therapies for a subgroup of breast cancer patients who have significant PSA concentrations in their tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005947024666
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  • 81
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    Tumor oxygenation correlates with molecular growth determinants in breast cancer (1998)
    Springer
    Breast cancer research and treatment 48 (1998), S. 97-106 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; oxygen partial pressure ; molecular markers ; prognostic factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hypoxic tumor cells may represent a fraction of cells that are not susceptible to radiation or chemotherapy. Intratumoral oxygen partial pressure (pO2) is the result of oxygen delivery and consumption. Cell proliferation is one factor to effect oxygen consumption and we therefore studied the correlation between tumor pO2 and histological parameters. Patients and methods: In 36 women and one man (age range 29–80 years) with suspected breast cancer. Before tumor resection, intralesional pO2 was determined with a polarographic needle electrode. Under ultrasound control, 200 tumor measurements were obtained; Hb levels, Hk, arterial blood gas parameters, and tissue temperature were determined. The median of pO2 values and the percentage of hypoxic areas (pO2 〈 10 mmHg) were calculated and correlated with the histological type, grading, ER, PR, and the expression of Ki-67, p53, EGFR, pS2, and c-erb-B2. Results: The overall median pO2 was 44 mmHg, and 1024 measurements (13.8%) represented hypoxic areas. Ductal and lobular invasive cancers showed median pO2 of 41 mmHg. The mean pO2 of G1 tumors was 59 mmHg and the hypoxic fraction 8%, in contrast to G2 tumors with 43 mmHg and 17%, and G3 tumors with 36 mmHg and 20.4% (p 〈 0.01). We observed a correlation with tumor size and an increased rate of hypoxic areas in T3–4 lesions (p 〈 0.02). Also tumors with negative nodes or positive ER had significantly higher pO2 values, as did tumors with an overexpression of c-erb-B2, p53, and cathepsin D. Conclusion: Oxygenation of human breast cancers can safely be measured in patients prior to surgical therapy. pO2 values correlate both with prognostic markers examined histologically and with molecular growth factors. As the efficacy of preoperative or adjuvant treatment in individuals may depend on oxygen partial pressure, efforts to manipulate tumor pO2 for therapeutic purpose could be promising.
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    URL: http://dx.doi.org/10.1023/A:1005921513083
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  • 82
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    Aneuploidy of chromosome 8 as detected by interphase fluorescence in situ hybridization is a recurrent finding in primary and metastatic breast cancer (1998)
    Springer
    Breast cancer research and treatment 48 (1998), S. 125-133 
    Details
    ISSN: 1573-7217
    Keywords: aneuploidy ; breast cancer ; FISH ; interphase cytogenetics ; metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous work from our laboratory demonstrated aneuploidy for several chromosomes by interphase fluorescence in situ hybridization (FISH) in a high proportion of breast cancer specimens. In the literature, only limited data are available concerning chromosome 8 anomalies in breast cancer. To determine chromosome 8 ploidy status in primary and metastatic specimens from 81 breast cancer patients, FISH analysis with a DNA probe recognizing chromosome 8 centromeres was performed. In all primary tumor specimens (n=30), significant proportions of cells were aneuploid exhibiting gain of chromosome 8 copy numbers; in 75% of effusion specimens previously classified as malignant by cytology and/or FISH for various chromosomes (n=40), cell populations aneuploid for chromosome 8 were detected; effusions previously classified non-malignant (n=11) were diploid in 10 cases, whereas one specimen contained rare hyperdiploid cells. Among these cells complex chromosomal aneuploidy could be demonstrated by two-color FISH, suggesting malignancy. Trisomic and tetrasomic clones were predominant in the majority of samples, but a marked intratumor cytogenetic heterogeneity was observed in most cases. Primary tumors and corresponding positive axillary lymph nodes revealed similar distributions of chromosome 8 copy numbers, analogous to previous findings with other chromosomes. This implies that, by using suitable FISH probes after examination of the respective primary tumor, an efficient search for (micro)metastasis might be feasible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005937305102
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  • 83
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    Prevention of development of dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat by the new nonsteroidal antiestrogen EM-800 (SCH57050) (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 1-11 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; antiestrogen ; estrogen-sensitive ; bone mineral density ; lipids ; BMD ; cholesterol ; triglycerides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of EM-800, a new non-steroidal antiestrogen having pure antiestrogenic activity, was studied on chemical carcinogenesis induced by dimethylbenz(a)anthracene (DMBA) as well as on serum lipids and bone mass in the rat. Treatment with EM-800 orally, once daily, for 282 days (9 months), starting 3 days before DMBA administration, decreased the incidence of tumors from 95% in control animals to 60% (p 〈 0.01), 38% (p 〈 0.01), and 28% (p 〈 0.01) at the daily doses of 25 μg, 75 μg, and 250 μg, respectively. The average number of tumors per animal decreased from 4.5 ± 0.5 tumors in the control group to 0.9 ± 0.2 (p 〈 0.01), 0.5 ± 0.2 (p 〈 0.01), and 0.3 ± 0.1 (p 〈 0.01) tumors in the rats treated with the above-indicated doses of the antiestrogen. In addition, treatment with the increasing doses of EM-800 reduced serum cholesterol levels to 64%, 56%, and 48% of control, while serum triglycerides decreased to 31%, 28%, and 30% of control. Bone mineral content (BMC) and bone mineral density (BMD) of total skeleton, femur, and lumbar spine were not significantly affected following 282 days of treatment with EM-800. However, treatment with EM-800 inhibited the urinary ratio of hydroxyproline to creatinine (HP/Cr) from 14.0 ± 3.90 μmol/mmol in controls to 7.6 ± 0.8 (p 〈 0.05), 6.8 ± 0.8 (p 〈 0.01), and 6.8 ± 1.1 (p 〈 0.01) μmol/mmol, respectively, while the same treatment had no effect on serum total alkaline phosphatase (tALP) activity or urinary calcium and phosphorus excretion. The 25 μg, 75 μg, and 250 μg daily doses of EM-800 inhibited uterine weight by 35% (p 〈 0.01), 62% (p 〈 0.01), and 66% (p 〈 0.01), while vaginal weight was reduced by 8% (p 〈 0.05), 30% (p 〈 0.01), and 38% (p 〈 0.01), respectively. In agreement with the 27% increment (p 〈 0.05) in ovarian weight at the highest antiestrogen dose used, serum androstenedione (p 〈 0.05), androst-5-ene-3β,17β-diol (p 〈 0.01), testosterone (p 〈 0.05), and estradiol (p 〈 0.01) levels were increased. The present data show that EM-800 prevents the development of DMBA-induced mammary tumors while simultaneously inhibiting uterine and vaginal weight, reducing serum cholesterol and triglyceride levels, and having no adverse effect on bone mass following 9 months of treatment in the rat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005928814521
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  • 84
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    The intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine.HCl, may potentiate doxorubicin in the treatment of metastatic breast cancer: Results of a pilot study (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 61-68 
    Details
    ISSN: 1573-7217
    Keywords: doxorubicin ; breast cancer ; potentiation ; DPPE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine.HCl (DPPE) is a diphenylmethane analog of tamoxifen that antagonizes the intracellular binding of histamine to growth-regulatory sites, a proportion of which represents P450 enzymes, in microsomes and nuclei. We previously reported increased response rates and decreased myelotoxicity in patients with prostate and other cancers who received an intensive dose/schedule of DPPE plus single-agent chemotherapy. We now report the results of a study of DPPE combined with a standard dose/schedule of doxorubicin in twenty-three patients with metastatic breast cancer, sixteen of whom had received prior non-anthracycline chemotherapy. DPPE (6 mg/kg) was infused intravenously (IV) over 80 minutes. Doxorubicin (60 mg/m2) was administered IV over the last 20 minutes of the DPPE infusion. Treatment was repeated every 3 weeks (maximum, 7 cycles). Patients achieving complete response (CR) were followed off treatment until relapse. All patients were evaluable for toxicities and efficacy. Sixteen patients (69%; 95% C.I. = 47–87%) responded (7 CR and 9 PR). Eleven responders, including 6 with CR, had prior chemotherapy. Five responders (2CR, 3PR) had a poor (ECOG 3/4) performance status pre-treatment. Median CR duration was 11 (range 5–18) months. Hematological toxicity was low; GI toxicity (nausea/vomiting/dyspepsia) appeared somewhat higher than historical experience, but responded well to anti-emetics, ranitidine, and/or dexamethasone in most patients; a mean absolute drop in left ventricular ejection fraction of 8% occurred in 17 patients who received ⩾ 300 mg/m2 doxorubicin. The observed response rate in DPPE/doxorubicin-treated patients appeared to be higher than historically reported for doxorubicin alone in this setting, suggesting a chemopotentiating effect of DPPE. A multi-centre trial of this regimen in an additional 32 patients with early metastatic breast cancer has been conducted by the Clinical Trials Group, National Cancer Institute of Canada, and a phase 3 study is planned.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005909808529
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  • 85
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    Electronic Resource
    Outcome of treatment for ipsilateral breast tumor recurrence in early-stage breast cancer (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 69-78 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; ipsilateral breast tumor recurrence ; prognosis ; uncontrolled local disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Introduction: The aims of the study were to assess the outcome among patients with early breast cancer operated on with wide local excision who developed a subsequent ipsilateral breast tumor recurrence, and to identify risk factors for uncontrolled local disease. Uncontrolled local disease (ULD) was defined as the appearance of clinically manifest invasive adenocarcinoma in the remaining breast or on the ipsilateral chest wall which could not be eradicated with salvage treatment during the period of follow-up (2–18 years). Patients and methods: Eighty-five patients in a cohort of 759 patients, treated for invasive Stage I–II breast cancer with breast-conserving surgery 1976–1985 in Stockholm, with a subsequent ipsilateral breast tumor recurrence (IBTR) were reviewed retrospectively. The majority of the patients were premenopausal (58%), node negative (72%), and had received postoperative radiotherapy (79%). Median follow-up time following breast-conserving surgery was 13 (9–19) years. Multivariate Cox's hazard regression was used in the statistical analysis to identify prognostic factors for ULD. Results: The majority (n = 61) of the IBTR's were located in the original tumor quadrant and showed the same histopathological features as the primary tumor. Salvage mastectomy (n = 65) or reexcision (n = 14) were performed in 79 (93%) of the patients. Twenty-one patients developed ULD. Five years following the diagnosis of IBTR the disease-free survival was 59%, the cumulative incidence for ULD was 24%, and for death in breast cancer 34%. In the cohort of 759 patients, patients who received radiotherapy following the primary breast-conserving surgery had 1% cumulative incidence of ULD following the diagnosis of IBTR compared to 4% among patients that received no postoperative radiotherapy. The cumulative incidence at 5 years of ULD following salvage mastectomy was 12% compared to 33% after salvage reexcision. Patients operated on with breast-conserving surgery with an original tumor size 〈 15 mm, who were treated with salvage mastectomy for IBTR, had in multivariate analysis the lowest relative risk for ULD. Adjuvant chemotherapy following IBTR treatment did not seem to improve local tumor control. Following the diagnosis of IBTR, 78% (n = 21) of the patients with ULD and/or regional recurrence (n = 27), died of a disseminated breast cancer in contrast to 10% (n = 6) among the remaining 58 patients. Conclusion: Uncontrolled local disease is an important outcome measure following breast-conserving surgery. In this cohort, salvage mastectomy provided a superior local control rate compared to salvage reexcision. A higher although not statistically significant rate of ULD was also seen in patients who had not received postoperative radiotherapy as part of their primary treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005934513072
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  • 86
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    Electronic Resource
    The incidence of microsatellite instability and loss of heterozygosity in fibroadenoma of the breast (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 165-169 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; fibroadenoma ; loss of heterozygosity ; microsatellite instability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A majority of studies have shown an increase in the risk of breast cancer among women previously diagnosed with fibroadenoma (FA). At present there is conflicting evidence whether some of the chromosome abnormalities frequently found in breast carcinoma, such as loss of heterozygosity (LOH), are already present in FAs and other types of benign breast disease and, if present, whether such abnormalities are associated with the observed increase in risk. Microsatellite instability (MSI) is also recognised as a marker of genetic damage and is thought to occur when there has been damage to the cell's mismatch repair (MMR) system. We have analysed 39 cases of FA obtained from paraffin-embedded tissue for the presence of MSI and LOH at 11 loci to determine if these types of genetic alterations occur in FA. The incidence of MSI and LOH found were 4 of 395 (1.0%) and 5 of 271 (1.8%) informative loci tested respectively. Approximately 8% of cases were positive for MSI and 10% were positive for LOH, with one specimen having multiple occurences of both MSI and LOH. We conclude that these forms of genetic alteration do occur in FAs but that the incidence is low.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005930429002
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  • 87
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    Electronic Resource
    Galectin-3 and L1 retrotransposons in human breast carcinomas (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 171-183 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; galectin-3 ; Line 1 retrotransposon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Galectin-3 is a galactoside binding protein found at elevated levels in a wide variety of neoplastic cells and thought to be involved in cognitive cellular interactions during transformation and metastasis. Previously, we have shown that introduction of human galectin-3 (Mr 31,000) cDNA into the human breast cancer cells BT-549 which are galectin-3 null and non-tumorigenic in nude mice resulted in the establishment of four galectin-3 expressing clones. Three of them acquired tumorigenicity when inoculated in the mammary fat pad of nude mice. Here, we questioned what is the molecular difference between the nude mouse tumorigenic and non-tumorigenic galectin-3 expressing BT-549 cell clones. Differential display analysis and Northern blotting revealed that, unlike the tumorigenic clones, neither the parental cells nor the non-tumorigenic clone expressed a 6.5 Kb transcript. A 607 bp PCR (polymerase chain reaction) product from the differentially displayed mRNA revealed a 93% sequence homology with the human L1 retrotransposon previously suggested to play a role in the pathobiology of some breast cancers. In addition, we show that the two gene products, i.e., galectin-3 and L1, are co-expressed in breast carcinoma specimens and in other nude mouse tumorigenic cell lines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005913810250
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  • 88
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    Electronic Resource
    Fractal analysis of mammographic lesions: A prospective, blinded trial (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 245-249 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; fibroadenoma ; fibrocystic disease ; fractal analysis ; mammography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Mammography has become the mainstay of breast cancer screening. However, widespread mammography has led to an increase of the number of breast biopsies done for benign disease. Therefore, a method to better discriminate benign from malignant lesions is needed. Fractal analysis is a mathematical method which can quantify complex shapes. It has been previously shown retrospectively that the composite fractal dimensions, D, of malignant mammographic masses is higher than for benign lesions. A prospective study of 75 patients who were recommended to undergo needle localized breast biopsy by independent radiologists had the composite D calculated. Fractal analysis was done without knowledge of the biopsy results. The mean composite D of malignant lesions was higher than benign lesions, 2.545 ± 0.067 vs. 1.936 ± 0.144 (p=0.00004). Calculation of a receiver-operating characteristic curve showed that a cutoff value of 2.067 had a 100% sensitivity and 63% specificity (i.e., false positive rate of 37%). Mean D for fibroadenomas was 2.087 ± 0.054, fibrocystic disease was 1.877 ± 0.167, DCIS was 2.261 ± 0.069, and invasive cancer was 2.634 ± 0.039 (1-way ANOVA, p=0.00007). These data imply that fractal analysis may be beneficial in discriminating between benign and malignant lesions. However, further study in a larger number of patients with a variety of lesions is needed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006093309091
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  • 89
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    Electronic Resource
    Fibrotic focus in infiltrating ductal carcinoma of the breast: A significant histopathological prognostic parameter for predicting the long-term survival of the patients (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 195-208 
    Details
    ISSN: 1573-7217
    Keywords: infiltrating ductal carcinoma ; breast cancer ; histology ; fibrotic focus ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The presence of fibratic fows (FF) in infiltrating ductal carcinoma (IDC) has been shown to be an important histological factor associated with high tumor aggressiveness, or early tumor recurrence or death. However, the clinicopathological significance of FF for predicting the long-term survival of the patients with IDC has not been fully investigated. In order to elucidate this aspect, we divided 140 IDCs with at least 10 years of follow up into tumors with FF and those without. IDC with FF showed significantly higher histologic grade (P=0.02), higher frequency of tumor necrosis (P=0.02), higher frequency of cases with more than three positive lymph node metastases (P=0.04), higher T classification (P=0.009), and higher pathological stage (P=0.0002) than those without FF. Relative risk (RR) of tumor recurrence and death was significantly higher in tumors with FF than in those without (RR=4.5, P 〈 0.00001 and RR=5.6, P 〈 0.00001, respectively). In cases of early stage cancer (stages I, IIA, and IIB), or in those with less than four lymph node metastases, IDCs with FF demonstrated a significantly higher risk than those without. Multivariate adjustments for other pathological factors did not change the RRs significantly. These results indicate that in long-term follow up the presence of FF is a significant prognostic parameter for IDC, and therefore strongly suggest that IDCs must be divided into those with and without FF.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006067513634
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  • 90
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    Electronic Resource
    Predictive value of SRC-1 for tamoxifen response of recurrent breast cancer (1998)
    Springer
    Breast cancer research and treatment 48 (1998), S. 87-92 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; SRC-1 ; RT-PCR ; response ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tamoxifen causes an objective response in about one-third of metastatic breast cancer and in only half of the breast cancer patients with estrogen receptor (ER) positive tumors. Steroid-receptor coactivator-1 (SRC-1) appears to be a general coactivator for steroid receptors and rate limiting factor necessary for efficient ER transactivation. We aimed to evaluate whether SRC-1 expression is an additional factor for prediction of response to first-line tamoxifen therapy in patients who developed recurrent disease. Here for the first time, we report on SRC-1 expression using a semi-quantitative RT-PCR in 21 primary breast tumors, seven mammary tumor cell-lines, 12 fibroblast cultures, and six normal breast tissues. The highest levels of SRC-1 were observed in normal tissues, intermediate levels in tumor tissues, and the lowest levels in breast tumor cell-lines. There was no relationship between the levels of SRC-1 in these primary tumors and the proportion of tumor cells within the surgical samples, nor with ER status. The median SRC-1 level was, however, lower in tumors from patients that did not respond to tamoxifen. Our findings suggest that high levels of SRC-1 indicate a favorable response to tamoxifen of patients with recurrent breast cancer. Abbreviations: PgR, progesterone receptor; ER, estrogen receptor; GR, glucocorticoid receptor; TR, thyroid hormone receptor; RXR, retinoid X receptor; SRC-1, steroid-receptor coactivator-1; EGF, epidermal growth factor; TGF, transforming growth factor; IGF, insulin like growth factor; UPA, urokinase-type plasminogen activator
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005903226483
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  • 91
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    Electronic Resource
    Effect of retinoid analogues on mammary cancer in transgenic mice with c-neu breast cancer oncogene (1998)
    Springer
    Breast cancer research and treatment 48 (1998), S. 265-271 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; c-neu transgenic mice ; N-(4-hydroxyphenyl) retinamide ; arotinoid Ro 40-8757 ; retinoid analogues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Breast cancer is one of the most common cancers and is a leading cause of mortality in women. The TG.NK transgenic mouse line expresses the c-neu breast cancer oncogene under the control of an MMTV promoter and appears to be a useful animal model for evaluation of intervention strategies to delay/prevent breast cancer. Fiber-rich nonpurified diet (NTP-2000), as compared to a purified diet (AIN-76A), has previously been shown to significantly delay the development of mammary cancer in the TG.NK model. Four-week old hemizygous TG.NK female mice with MMTV/c-neu oncogene were fed NTP-2000 diet containing the retinoid analogue 4-hydroxyphenyl retinamide (4-HPR) at 5 mM/kg or an arotinoid Ro 40-8757 at 2 and 3 mmol/kg for 26 weeks. The 4-HPR at 5 mmol/kg diet delayed the development of palpable tumors up to 24 weeks, but by 26 weeks, the incidence was not significantly different from the NTP-2000 diet control group. However, the 4-HPR diet markedly decreased the average weight of the tumors at 26 weeks. The 4-HPR diet also caused a significant increase in body weight without an increase in food consumption. Arotinoid Ro-40-8757 at both doses inhibited the development of mammary tumors for the duration of the study. However, the Ro 40-8757 at 3 mmol/kg appeared to be toxic as indicated by a significant depression of the average body weight with alopecia and skin scaling in some mice. Our observations with TG.NK transgenic mouse and fiber-rich diet (NTP-2000) indicate that the arotinoid Ro 40-8757 has a markedly higher inhibitory effect on the development of mammary cancer than 4-HPR. Studies to evaluate genetic changes and expression of hormonal receptors and growth factors associated with the inhibition of mammary cancer development by the retinoid analogues are in progress.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005957620881
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  • 92
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    Electronic Resource
    Therapeutic potential of recombinant p53 overexpression in breast cancer cells expressing endogenous wild-type p53 (1998)
    Springer
    Breast cancer research and treatment 48 (1998), S. 273-286 
    Details
    ISSN: 1573-7217
    Keywords: adenoviral vectors ; apoptosis ; breast cancer ; gene therapy ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Reconstitution of the p53-dependent apoptotic pathway by gene transfer of a recombinant wild-type p53 minigene leads to rapid apoptotic cell death in breast and other cancer cell types expressing null or mutant p53. Tumour cells expressing wild-type p53 have been reported to be more resistant to this treatment strategy, presumably as a result of mutations in downstream regulators of p53-dependent apoptotic signalling. The MCF-7 breast cancer cell line is representative of this class of tumour cell. Our recent observation of a p53-dependent apoptotic response following adenovirus-mediated HSV thymidine kinase gene transfer and gancyclovir treatment led us to reexamine recombinant p53 cytotoxicity in MCF-7 cells. Infection with a recombinant adenovirus expressing wild-type p53 resulted in a dramatic increase in p53 protein levels and was accompanied by an increase in p21WAF 1/CIP1 protein levels and G1 arrest within 24 hours post-infection. A significant decrease in MCF-7 cell viability was first observed at 5 days post-infection and coincided with the appearance of morphological and biochemical changes consistent with apoptotic cell death. By day 7 post-treatment, cell viability decreased to 45% and clonogenic survival was reduced to 12% of controls. The results demonstrate that persistent, high level expression of recombinant p53 can induce programmed cell death in MCF-7 cells. While the mechanism by which p53 overexpression overcomes the defect in downstream apoptotic signalling is not clear, our data suggests that this treatment strategy may be beneficial for the class of tumour cells represented by the MCF-7 cell line.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005961705860
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  • 93
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    Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 41-50 
    Details
    ISSN: 1573-7217
    Keywords: uPA ; PAI-1 ; uPAR ; plasma ; menstruation ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The plasma urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator receptor (uPAR) levels were measured in healthy volunteers and breast cancer patients. In pre-menopause healthy females, blood was sampled weekly during one menstruation cycle and menstruation phases (follicular, ovulatory, luteal) were determined by FSH/LH levels. uPA, PAI-1, and uPAR levels were at the nadir during ovulatory phase. uPA level was highest at follicular phase while PAI-1 level was highest at luteal phase. In comparison between pre- and post-menopause states, uPA and uPAR levels were higher in post-menopause state while PAI-1 level was higher in pre-menopause state. In breast cancer patients, uPA, PAI-1, and uPAR positive rates were low when we use the menopause-state-unmatched cut-off points. As we adjusted the cut-off points by menopause states, the PAI-1 positivity increased mainly in post-menopause cancer patients. These findings suggest that there is a minor but possible sequential change of these molecules during menstruation cycle which might blur the pathological positivity in pre-menopause cancer patients. The pathological elevation of PAI-1 was well detected in post-menopause cancer patients, but this elevation did not correlate with tumor burden such as number of metastatic sites or metastatic location. In conclusion, adjustment of physiological changes of uPA, PAI-1, and uPAR is required in determining pathological elevation of the plasma levels in cancer patients, especially in females.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005997421733
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  • 94
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    Direct comparisons of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer patients stratified by estrogen receptor and menopausal status (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 51-60 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; adjuvant therapy ; endocrine therapy ; chemotherapy ; chemoendocrine therapy ; randomized trial ; estrogen receptors ; menopause
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Based on estrogen receptor (ER) and menopausal status, operable breast cancer (UICC stage I, II, III-a) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the relapse-free survival (RFS) and overall survival (OS) were compared. Tamoxifen (TAM) 20 mg/day was administered orally for 2 years after mastectomy as an adjuvant endocrine therapy in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was performed before TAM administration. In the chemotherapy arm (CHEM), patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously, followed by an oral administration of cyclophosphamide (CPA) 100 mg/day in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated 4 times in 2 years. The chemoendocrine arm (CHEM + TAM) was composed of TAM with MMC + CPA chemotherapy. The patients were randomized according to ER and menopausal status. ER-positive patients were randomized to three arms: OVEX ± TAM, CHEM, and CHEM + TAM. For ER-negative patients there were two arms: CHEM and CHEM + TAM. 1579 patients entered the trial between September 1978 and December 1991, with median follow-up of 8.2 years. In ER-positive, premenopausal patients, there were no significant differences in RFS or OS among OVEX ± TAM, MMC + CPA, TAM + MMC + CPA arms. On the contrary, in ER-positive, postmenopausal patients, the chemoendocrine therapy showed a significantly higher RFS (p = 0.0400) and OS (p=0.0187) as compared with TAM to chemotherapy alone. There were no significant differences in RFS or OS by addition of TAM on the chemotherapy, in both pre- and post-menopausal ER-negative patients. It was concluded that in ER-positive premenopausal breast cancer, endocrine therapy alone may be equivalent in prolonging RFS and OS to chemotherapy or chemoendocrine therapy, and that ER-positive postmenopausal breast cancer may be better controlled with the combination of TAM and chemotherapy, as compared to TAM or chemotherapy alone. The importance of stratification of operable breast cancer by ER and menopausal status, as well as the direct comparisons of different treatments, were stressed.
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    URL: http://dx.doi.org/10.1023/A:1005901622642
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  • 95
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    Electronic Resource
    Antisense depletion of RIα subunit of protein kinase A induces apoptosis and growth arrest in human breast cancer cells (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. 97-107 
    Details
    ISSN: 1573-7217
    Keywords: antisense ; protein kinase A ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In recent years, several laboratories have explored the possibility of using antisense oligodeoxynucleotides for specific manipulation of gene expression leading to cancer treatment. The enhanced expression of the RIα subunit of cyclic AMP-dependent protein kinase type I (PKA-I) has been correlated with cancer cell growth. In the present study, the effects of an antisense oligodeoxynucleotide targeted against RIα subunit of PKA-I on growth inhibition and apoptosis in MDA-MB-231 human breast cancer cells were investigated. The growth inhibitory effects of RIα antisense oligodeoxynucleotide correlated with a decrease in the RIα mRNA and protein levels. The growth inhibition was accompanied by changes in the cell cycle phase distribution, cell morpbology, cleavage of poly (ADP-ribose) polymerase (PARP), and appearance of apoptotic nuclei. By comparison, mismatched control oligodeoxynucleotide had no effect. On the basis of these results, it can be suggested that the RIα antisense oligodeoxynucleotide, which efficiently depletes the growth stimulatory RIα and induces apoptosis/differentiation, could be used as a therapeutic agent for breast cancer treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005905723550
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  • 96
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    Electronic Resource
    Tamoxifen aziridine binding to cytosolic proteins from human breast specimens is negatively associated with estrogen receptors, progesterone receptors, pS2, and cathepsin-D (1998)
    Springer
    Breast cancer research and treatment 50 (1998), S. 155-166 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; estrogen receptors ; progesterone receptor ; pS2 ; cathepsin-D ; native receptor ; tamoxifen aziridine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract [3H]Tamoxifen Aziridine ([3H]TAZ) is a derivative of the antiestrogen tamoxifen that covalently labels the Estrogen Receptor (ER), and perhaps other uncharacterized proteins. In a previous article we described that [3H]TAZ binds to a cytosolic protein from human uterine tissues that shares some, but not all, the ER properties. Here we have extended these studies to [3H]TAZ binding to cytosol proteins from human breast cancer specimens, and studied its quantitative association with other molecular markers and clinico-pathological variables. Cytosols were obtained in hypotonic buffer containing 20 mM molybdate and protease inhibitors, incubated with [3H]TAZ, and subjected to Sucrose Gradient Analysis (SGA). A [3H]TAZ labeled peak that consistently migrated with the 4S fractions was found in most of the assayed cytosols (range of 0 to 1278 fmol/mg p.). The 4S peak of [3H]TAZ was partially inhibited by both estrogens and antiestrogens. When [3H]E2 was used instead of [3H]TAZ, only an 8S peak was detected. [3H]TAZ was covalently bound to a protein with an apparent MW of 65 kDa, as determined by SDS-PAGE and fluorography. The mean of [3H]TAZ binding was significantly higher in the subgroups of samples classified as ER-, PR-, pS2- or cathepsin D-, than in the respective positive subgroups (P 〈 0.01 in all the cases). [3H]TAZ binding was not associated with clinico-pathological variables, except that its mean was significantly larger in tumors larger than 5 cm than in smaller tumors. These results, and those previously reported, suggest that: 1) [3H]TAZ labels a cytosolic protein present in human breast cancers and uterine tissues that does not share all the ER properties, and 2) the [3H]TAZ binding by breast cancer cytosols is negatively associated with markers of estrogenic dependency, and its quantification may provide valuable information on antiestrogen responsiveness of a given tumor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006062510883
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  • 97
    Electronic Resource
    Electronic Resource
    Additive effect of mifepristone and tamoxifen on apoptotic pathways in MCF-7 human breast cancer cells (1998)
    Springer
    Breast cancer research and treatment 51 (1998), S. 149-168 
    Details
    ISSN: 1573-7217
    Keywords: apoptosis ; bcl2 ; mifepristone ; PKC ; tamoxifen ; TGFβ1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract MCF-7 cells growing in culture were used to study the mechanism of the antiproliferative activity of the antiprogestin mifepristone, as compared with the antiestrogen 4-hydroxytamoxifen or the combination of both. These steroid antagonists induced a significant time- and dose-dependent cell growth inhibition (cytotoxicity). This inhibition of cell survival was associated with a significant increase in DNA fragmentation (apoptosis), downregulation of bcl2, and induction of TGFβ1 protein. Abrogation of the mifepristone- and/or 4-hydroxytamoxifen-induced cytotoxicity by TGFβ1 neutralizing antibody confirms the correlation between induction of active TGFβ1 and subsequent cell death. The effect of a combination of mifepristone and 4-hydroxytamoxifen on cell growth inhibition, on the increase in DNA fragmentation, bcl2 downregulation, and induction of TGFβ1 protein was additive and significantly different (P 〈 0.05) from the effect of monotherapy. A translocation of protein kinase C (PKC) activity from the soluble to the particulate and/or nuclear fraction appeared to be also additive in cells treated with a combination of both 4-hydroxytamoxifen and mifepristone. These results suggest that the mechanism of the additive antiproliferative activity of mifepristone and tamoxifen could be explained at least in part by an additive induction of apoptosis in both estrogen and progesterone receptor positive MCF-7 breast cancer cells. A bcl2 downregulation, the PKC transduction pathway, and TGFβ1 expression seem to be involved in this additive mechanism of action. Our data further suggest that a combination of an antiprogestin with tamoxifen may be more effective than tamoxifen monotherapy in the management of human breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006078032287
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  • 98
    Electronic Resource
    Electronic Resource
    Suspected spinal cord compression in breast cancer patients: A multidisciplinary risk assessment (1998)
    Springer
    Breast cancer research and treatment 51 (1998), S. 121-131 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; metastases ; models ; retrospective studies ; risk ; spinal cord compression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Breast cancer is the most common cause of metastatic epidural spinal cord compression (SCC) in women, and this condition results in significant neurologic dysfunction and morbidity. Prior studies of patients with suspected SCC did not employ multivariate analysis techniques, often included persons with a wide variety of malignancies, and generally focused on identifying associated neurologic and radiologic features. We therefore conducted a study examining a more comprehensive set of potential clinical risk factors in breast cancer patients with suspected SCC. We retrospectively analysed 123 episodes of suspected SCC among 93 breast cancer patients evaluated by spine computed tomography (CT) scanning. Multiple logistic regression analysis was employed to identify independent predictors of SCC. Clinically significant metastatic epidural cancer was defined as thecal sac compression (TSC), which occurred in 33 episodes (27%). Four independent predictors of TSC were identified and included oncologic features (known bone metastases ≥ 2 years, metastatic disease at initial diagnosis) in addition to neurologic and radiologic features (objective weakness, vertebral compression fracture on spine radiograph). These four predictors stratified episodes into subgroups with widely varying risks of TSC, ranging from 12% (0 risk factors) to 85% (≥ 3 risk factors). These results suggest that the evaluation of breast cancer patients with suspected SCC should include clinical information about their disease course in addition to neurologic examination and prior imaging studies. If confirmed, these predictors may help clinicians assess risk in this patient population.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006002823626
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  • 99
    Electronic Resource
    Electronic Resource
    Prognostic factors for patients with breast cancers 1cm and smaller (1998)
    Springer
    Breast cancer research and treatment 51 (1998), S. 209-225 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; prognosis ; tumor size
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The widespread use of mammography has resulted in the detection of an increasing number of small invasive breast cancers,i.e. those that are 1cm and smaller. Patients with these small cancers generally have a low incidence of axillary lymph node metastases, and this has led to some to question the routine use of axillary dissection in these patients. In addition, the prognosis of these patients is generally favorable, and the routine use of adjuvant systemic therapy is difficult to justify. Nonetheless, some patients with these small invasive cancers will have axillary nodal involvement and/or develop metastatic disease. The identification of this prognostically unfavorable subset of patients within this otherwise favorable group is an important goal of clinical research. In this article, we review the available literature on prognostic factors for patients with breast cancers 1cm and smaller to help determine which of these features might be of value in the identification of patients at risk for axillary lymph node involvement and/or metastatic disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006130911110
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  • 100
    Electronic Resource
    Electronic Resource
    Aromatase expression in the human breast (1998)
    Springer
    Breast cancer research and treatment 49 (1998), S. S85 
    Details
    ISSN: 1573-7217
    Keywords: aromatase ; breast cancer ; normal breast immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The plasma levels of free estradiol are very low in postmenopausal women. However, concentrations of estrogens within breast tissue have been reported to be higher than in plasma and similar to plasma concentrations in premenopausal women. One mechanism by which this may occur is for breast cells to synthesize estrogens themselves and produce high concentrations locally. Thus, tumor aromatase may be a significant source of estrogen which stimulates tumor growth. To address the question of the importance of this pathway, we have investigated the expression of aromatase within the normal breast and breast cancers. Because conventional biochemical assays for measuring aromatase activity require relatively large amounts of tissue, we developed an immunocytochemical method using a monoclonal antibody to determine the expression of aromatase. The method can be applied to sections of tumors embedded in paraffin blocks as routinely prepared for pathology. Since we have previously shown that mRNA for aromatase (P450 arom) and the protein are expressed in the same cells of the human placenta, we used in situ hybridization of sequence specific probes to P450 arom mRNA in breast tissue as one method to verify the specificity of the immunocytochemical detection of the enzyme. Both immunocytochemistry and in situ hybridization identified aromatase enzyme and mRNA expression in the epithelial cells of the terminal ductal lobula units (TDLU) and surrounding stromal cells of the normal human breast, and in the tumor epithelial cells and stromal cells of breast cancers. In addition, evidence for the functional significance of tumor aromatase was indicated by a correlation between aromatase activity and expression of proliferating cell nuclear antigen (PCNA) in the tumor, and by increased thymidine incorporation into DNA in response to testosterone in tumors in histoculture which had high aromatase activity but not in those with low activity. The findings suggests that estrogen produced locally is important in enhancing proliferation of the tumor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006029612990
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