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  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 9 (1998), S. 139-149 
    ISSN: 1569-8041
    Schlagwort(e): asbestos ; chemotherapy ; epidemiology ; malignant mesothelioma ; photodynamic therapy ; radiation therapy ; surgery
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 2
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; extranodal lymphoma ; MALT lymphomas ; ocular adnexal lymphomas ; radiotherapy ; survival
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: The aim of this study was to assess clinicopathological characteristics and outcome in a series of primary ocular adnexal lymphomas (POALs). Patients and methods: Nineteen patients with localised (stage IE) POAL were followed for a median of 96 months (24–156). The diagnosis was based on surgical biopsies followed by immunohistochemistry in 16 cases or fine-needle aspiration followed by immunocytophenotypic analysis in three cases. Twelve patients were treated with local radiotherapy (RT), five with chemotherapy (CT), and two refused further therapy after apparently radical tumour removal achieved by the diagnostic excisional biopsy. Results: The histological and immunological pattern was consistent with a diagnosis of MALT-type lymphoma (11 cases), follicular center non-Hodgkin's lymphoma (three cases), a large-cell variant of Burkitt's lymphoma (one case), and large-cell transformed MALT lymphoma (one case). Low-grade lymphoma was diagnosed in the three cases which underwent fine-needle aspiration biopsy. All of the patients achieved and maintained complete remission except for those treated with surgical excision alone (two MALT conjunctival lymphoma cases): one of these relapsed locally, the other experienced the systemic spread of a transformed diffuse large-cell lymphoma and died 72 months after diagnosis. The side effects consisted of two cases of RT-related cataract after 52 and 72 months. Conclusions: Regardless of histology, prognosis was excellent when surgery plus RT was adopted, and CT seems to be a valid alternative to RT. Surgery alone may be sub-optimal.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; grading ; peripheral neurotoxicity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Reliable reporting of chemotherapy-induced neurotoxicity is important. The objectives of the current study were to evaluate the differences in the peripheral neurotoxicity sections of several widely used chemotherapy-related toxicity grading systems, and the differences in the way in which observers interpret these scales. Patients and methods: Two neurologists independently rated the severity of chemotherapy-induced peripheral neuropathy, according to WHO, ECOG, Ajani, and NCIC-CTC criteria in 37 patients. Results: The highest percentage grade 1, grade 2 and grade 3 peripheral neurotoxicity was noted when employing the WHO, Ajani and NCIC-CTC scales, respectively. Percentage interobserver agreement across all grades of severity ranged from 45.9 (NCIC-CTC) to 83.8 (WHO). The degree of agreement varied from ‘poor to fair’ to ‘substantial’. Percentage interobserver agreement for the dichotomy grade ≤2 and grade 3 ranged from 81.1 (NCIC-CTC) to 94.6 (Ajani and WHO), however, exact agreement on grade 3 peripheral neurotoxicity ranged from 0 (Ajani and WHO) to 42% (NCIC-CTC). Percentage interscale agreement for the dichotomy grade ≤2 and grade 3 varied from 67.6 (WHO and NCIC-CTC) to 100 (WHO and ECOG). Interobserver disagreement of severity grading was partly due to different interpretation of scale parameters. Conclusions: Our results suggest that caution should be used in interpreting results across studies using different scales for neurotoxicity grading in chemotherapy-related peripheral neuropathy. When (multicentre) trials are to be undertaken with potential neurotoxic or neuroprotective agents, consensus should be sought regarding the toxicity rating scale used, and its interpretation by participating physicians.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1569-8041
    Schlagwort(e): central venous catheters ; chemotherapy ; Groshong catheter ; ports
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: A few data are available from analyses of the complications and costs of central venous access ports for chemotherapy. This prospective study deals with the complications and global costs of central venous ports connected to a Groshong catheter for deliverance of long-term chemotherapy. Patients and methods: Patients with a variety of solid neoplastic diseases requiring chemotherapy who were undergoing placement of implantable ports over a 30-month period (1 October 1994 to 31 March 1997) have been prospectively studied. Follow-up continued until the device was removed or the study was closed (30 September 1997); patients with uneventful implant experience and subsequent follow-ups of less than 180 days were not considered for this study. A single port, constructed of titanium and silicone rubber (Dome Port™, Bard Inc., Salt Lake City, USA), was used, connected to an 8 F silastic Groshong™ catheter tubing (Bard Inc., Salt Lake City, USA). Two-hundred ninety-six devices were placed in the operating room under fluoroscopic control even in the patients treated and monitored in a day-hospital setting; 37 of them were in an angiographic suite. A central venous access form was filled in by the operator after the procedure and all ports were followed prospectively for device-related and overall complications. The average purchase cost of the device was obtained from the hospital charges, based on the costs applied during the 30-month period of the study. Insertion and maintenance costs were estimated by obtaining the charges for an average TIAP implant and its subsequent use; the costs of complication management were assessed analytically. The total cost of each device was defined as the purchase cost plus the insertion cost plus the maintenance cost plus the cost of treatment of the complications, if any. The cost of removing the TIAP was also included in the economic analysis when required by the treatment of the complication. Results: Three hundred thirty-three devices, for a total of 79,178 days in situ, were placed in 328 patients. Five patients received second devices after removal of the first. In all cases the follow-up was appropriate (median 237 days, range 180–732). Early complications included 10 pneumothoraxes (3.4%; six tube-thoracostomies were applied, 1.8%) and six revisions for port and/or catheter malfunction (overall early complications = 16, 4.48%). Late complications comprised five instances of catheter rupture and embolization (1.5%, 0.063 episodes/1000 days of use), five of venous thrombosis (1.5%, 0.063 episodes/1000 days of use), one of pocket infection (0.3%, 0.012 episodes/1000 days of use), and eight of port-related bacteremia (2.4%, 0.101 episodes/1000 days of use). The infections were caused by coagulase-negative Staphylococcus aureus (five cases), Bacillus subtilis (one case), Streptococcus lactaceae (one case) and an unknown agent (one case); port removal was necessary in six of eight cases. The total cost per patient treated for a six-month period, consisting of the costs of purchase and implantation, treatment of early and late complications, and of maintenance of the device, is US$1,970. Conclusions: This study represents the largest published series of patients with totally implantable access ports connected to a Groshong catheter. We have shown that US$2,000 are sufficient to cover six months of chemotherapy in one patient using the most expensive commercially available implantable port. According to the present study, totally implantable access ports connected to a Groshong catheter are associated with high purchase and insertion costs, a low complication rate and low maintenance costs. These data support their increasing use in current oncologic medical practice.
    Materialart: Digitale Medien
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  • 5
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; cisplatin ; ifosfamide ; intraarterial therapy ; osteosarcoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: In an effort to intensify osteosarcoma therapy, systemic ifosfamide was added pre- and postoperatively to an already aggressive three-drug regimen. In a subgroup of patients, loco-regional treatment intensification was attempted by using the intraarterial route to give cisplatin. Patients and methods: Patients ≤40 years at diagnosis of a localised, de novo high-grade central extremity osteosarcoma were eligible for inclusion into study COSS-86 if registered within three weeks from biopsy. Doxorubicin, high-dose methotrexate, and cisplatin were given to all patients. Patients who fulfilled one or more of three defined high-risk criteria received early systemic treatment intensification by adding ifosfamide as the fourth agent. Preoperatively, these high-risk patients received cisplatin either intraarterially or intravenously. Results: 171 eligible patients were entered, of which 128 were stratified into the high-risk group. When all 171 were analysed by intention-to-treat, actuarial overall and event-free survival rates at ten years were 72% and 66%, respectively. No benefit of intraarterial cisplatin application was detected. Cumulative treatment toxicity was considerable. Conclusions: In a multicenter setting, intensive treatment of osteosarcoma according to protocol COSS-86 led to long-term disease-free survival for two thirds of patients. We saw no benefit of using the intraarterial route to administer cisplatin.
    Materialart: Digitale Medien
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  • 6
    ISSN: 1569-8041
    Schlagwort(e): allograft ; autograft ; chemotherapy ; lymphoblastic lymphoma ; survival
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Objective: To describe the outcome of an unselected large series ofpatients with lymphoblastic lymphoma (LBL) treated in a single institution. Patients and methods: Sixty-two patients were treated between 1980 and1992. Induction chemotherapy (CT) to achieve complete response (CR) was:French Multicenter Acute Lymphoblastic Leukemia (ALL) protocols (38),non-Hodgkin‘s Lymphoma (NHL) protocols (20). Thirty patients underwenttransplant after achieving CR (allogeneic 12; autologous 18). Results: Forty-six patients (74%) achieved CR and 16 (26%)failed to respond. The patients who received an ALL induction had an89% CR rate, while the CR rate was 52% in patients whoreceived a NHL-like regimen. With a median follow-up of 93 months (range36–187), the actuarial overall survival (OS) rate for all patients is49% at five years and 41% at 10 years, and the actuarialevent-free survival (EFS) rate is 45% and 37%. OS and EFS inthe grafted population are, respectively, 60% and 56% at fiveyears. Our results also show a trend toward a longer OS in allograftedgroup. Conclusions: ALL induction therapy is more effective than the NHL-likeregimen for augmenting the CR rate. Autologous or allogeneic transplantationshould be considered as consolidation therapy in high-risk group patients.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1569-8041
    Schlagwort(e): biliary tract cancer ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: The combination of 5-fluorouracil (5-FU) and cisplatin hasshown great activity in many different types of tumour with an in vitrosynergistic effect between 5-FU and cisplatin. A phase II study of 5-FU pluscisplatin was performed in 25 previously untreated patients with inoperablelocally advanced or metastatic biliary tract carcinoma. Patients and methods: Twenty-five patients, 10 of them men and 15 womenwith a median age of 58, were entered into the study. The chemotherapyregimen consisted of 5-FU: 1 g/m2/day in continuousintravenous (i.v.) infusion for five consecutive days, and cisplatin: 100mg/m2/day on day 2 in a one-hour infusion with standardhyperhydration. Twenty-two patients had metastatic tumours and three hadlocally advanced disease. Results: Of the 25 patients entered into the study, 24 were evaluable forresponse and 25 for toxicity. Nausea and vomiting was the main toxic sideeffect in 19 patients. Severe, WHO grade 3–4 thrombocytopenia orneutropenia were observed in three and seven patients, respectively. Therewere no toxic deaths. Of 25 patients, six had partial remissions (overallresponse 24%, 95% confidence interval7%–41%). For three patients, tumour reduction permittedlocal radiotherapy and one of these patients with initially advanced diseaseis still alive six years after the beginning of treatment. Conclusions: This study, one of the largest phase II trials performed inthis disease, shows interesting activity of the combination of 5-FU andcisplatin in advanced biliary tract carcinoma.
    Materialart: Digitale Medien
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  • 8
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; cervical ; germ cell tumor ; prognosis ; surgery ; teratoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract We report a case of a man presenting with a cervical malignant teratoma and a chondrosarcomatous rib metastasis. He was alive and free of recurrence five years and 10 months (= 70 months) after resection of the primary mass, followed by chemotherapy and subsequent resection of the rib tumor. This is the 35th patient reported in the literature and the first description in which an ‘adjuvant’ or primary chemotherapy was used. Previous patients with a cervical malignant teratoma, reported after lethal outcome, had survivals of one to 22 months (median nine months). In all patients with a preoperative clinical impression of an aggressive, differentiated or undifferentiated malignancy, the definite diagnosis of teratoma could only be made histologically. By analogy to germ cell tumors, the prognosis of malignant teratoma might be improved if complete excision is combined with new, adjuvant chemotherapy protocols for germ cell tumors. Lessons learned from this case are placed in the context of germ cell tumors in general and of non-gonadal malignant teratomas in particular.
    Materialart: Digitale Medien
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  • 9
    ISSN: 1569-8041
    Schlagwort(e): breast cancer ; carboplatin ; chemotherapy ; paclitaxel
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
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  • 10
    ISSN: 1569-8041
    Schlagwort(e): carboplatin ; chemotherapy ; ovarian carcinoma ; paclitaxel
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Platinum compounds are the most active drugs in ovarian cancer treatment; cisplatin and carboplatin demonstrated similar efficacies but different toxicity profiles. Paclitaxel combined with cisplatin as first-line treatment improved overall survival when compared to a cisplatin-cyclophosphamide combination, but generated higher rates of neutropenia, febrile neutropenia and neurotoxicity. The paclitaxel-carboplatin combination may be better tolerated than cisplatin–paclitaxel. Design: The objective of the present study was to assess the efficacy and safety of the combination of paclitaxel and carboplatin in previously treated advanced ovarian cancer patients. Patients and methods: During or after platinum-based chemotherapy, 73 patients with progressive advanced epithelial ovarian carcinoma were enrolled to receive every four weeks a three-hour infusion of paclitaxel 175 mg/m2 followed by a 30-minute carboplatin infusion. The carboplatin dose was calculated to obtain the recommended area concentration-versus-time under the curve of 5 mg·ml-1·min. Results: Toxicity and response could be evaluated for 72 and 62 patients, respectively. Eleven complete and 15 partial responses gave an overall response rate of 42% (95% CI: 30%–54%). Response rates for platinum-refractory patients and those with early (≥3 and 〈12 months) and late (〉12 months) relapses were 24%, 33% and 70%, respectively. The respective median response duration, the median progression-free survival and median overall survival were 8, 6 and 14 months. Myelosuppression was the most frequent and severe toxicity. Grade 3 and 4 neutropenia occurred, respectively in 30% and 23% of the cycles; 6% of the cycles benefited from medullary growth factors. Only one episode of febrile neutropenia was observed. Grade 3 and 4 thrombocytopenia occurred, respectively during 3% and 1% of the cycles. Alopecia was frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death was attributed to progressive disease and possibly to therapy. Conclusion: This combined paclitaxel–carboplatin therapy is effective and can be safely administered to ovarian cancer patients who relapse after one or two regimens of platinum-based chemotherapy.
    Materialart: Digitale Medien
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  • 11
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; endpoint ; lung cancer ; phase II trial ; response rate
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Response rate (RR) has been used as a defining endpoint of new-agent phase II trials for non-small-cell lung cancer (NSCLC). However, tumor responses to chemotherapy do not always result in prolonged survival of patients with this disease. Design: Single-agent phase II trials were identified by a MEDLINE search of the period from 1976 to 1995. Associations between RR, median survival time (MST) and characteristics of patients who entered the trial, including tumor extent, performance status and prior chemotherapy, were studied by using the logistic regression model. Results: A total of 183 treatment arms in 176 trials (including 10 randomized phase II trials) were identified. The overall RR in the 6768 evaluable patients was 11%. Eleven drugs, cisplatin, epirubicin, ifosfamide, edatrexate, irinotecan, vinorelbine, docetaxel, paclitaxel, etoposide, vindesine, and 254-S, produced a RR of more than 20%. An MST of eight months or longer was obtained with 12 drugs, but there were cases in which no objective responses were produced by these drugs. MST was correlated with RR (r = 0.504, P 〈; 0.0001), but ranged broadly at a given level of RR. Multiple linear regression analysis showed a significant correlation between RR and MST (regression coefficient = 0.60, P = 0.00003) after adjustment for other variables. Conclusions: RR was significantly correlated with MST in single-agent phase II trials for NSCLC, but there is room for further consideration of the endpoint of these trials.
    Materialart: Digitale Medien
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  • 12
    ISSN: 1569-8041
    Schlagwort(e): breast cancer ; chemotherapy ; mastectomy ; neoadjuvant ; tamoxifen
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
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  • 13
    ISSN: 1569-8041
    Schlagwort(e): anemia ; chemotherapy ; malignancy ; recombinant human erythropoietin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Anemia is a common side effect of anticancer chemotherapy. Blood transfusion, previously the only available treatment for chemotherapy-induced anemia, may result in some clinical or subclinical adverse effects in the recipients. Recombinant human erythropoietin (rhEPO) provides a new treatment modality for chemotherapy-induced anemia. Patients and methods: To evaluate the effect of rhEPO on the need for blood transfusions and on hemoglobin (Hb) concentrations, 227 patients with solid tumors and chemotherapy-induced anemia were enrolled in a randomized, controlled, clinical trial. Of 189 patients evaluable for efficacy, 101 received 5000 IU rhEPO daily s.c., while 88 patients received no treatment during the 12-week controlled phase of the study. Results: The results demonstrate a statistically significant reduction in the need for blood transfusions (28% vs. 42%, P = 0.028) and in the mean volume of packed red blood cells transfused (152 ml vs. 190 ml, P = 0.044) in patients treated with rhEPO compared to untreated controls. This effect was even more pronounced in patients receiving platinum-based chemotherapy (26% vs. 45%, P = 0.038). During the controlled treatment phase, the median Hb values increased in the rhEPO patients while remaining unchanged in the control group. The response was seen in all tumor types. Conclusions: RhEPO administration at a dose of 5000 IU daily s.c. increases hemoglobin levels and reduces transfusion requirements in chemotherapy-induced anemia, especially during platinum-based chemotherapy.
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  • 14
    ISSN: 1569-8041
    Schlagwort(e): breast cancer ; chemotherapy ; lungs ; metastases
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
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  • 15
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 9 (1998), S. 589-600 
    ISSN: 1569-8041
    Schlagwort(e): brain neoplasms ; chemotherapy ; gene therapy ; glioma ; immunotherapy ; review literature
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Despite more than two decades of clinical research with chemotherapy, theoutcome of malignant gliomas remains poor. Recent years have seen majoradvances in elucidation of the biology of these tumors, which in turn haveled to the current development of innovative therapeutic strategies. Thequestion confronting us at the end of the 1990s is whether we shouldcontinue to use and investigate chemotherapy or whether the time has comefor experimental treatments. As a contribution to this debate, we reviewed the abundant literature onchemotherapy of malignant glioma, paying special attention to methodologicalfeatures. The new treatment approaches based on current knowledge aboutglioma biology are then briefly summarized. Assessment of more than 20 years of chemotherapy trials is discouragingdespite a few areas of modest success. Only patients with specific histology(oligodendroglioma, anaplastic astrocytoma) and good prognostic factors (youngage, good performance status) may benefit from chemotherapy, with a possiblereversal of neurological dysfunction. However, the real impact on survival issmall (anaplastic astrocytoma) or undefined (oligodendroglioma). Furthermore,it is unfortunately obvious that the outcome of glioblastoma patients is notsignificantly modified by chemotherapy. We believe the time has come toexplore the potential of novel biological therapies in glioblastoma patients.This could also be proposed for anaplastic astrocytoma and oligodendrogliomapatients after failure of chemotherapy.
    Materialart: Digitale Medien
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  • 16
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 9 (1998), S. 657-660 
    ISSN: 1569-8041
    Schlagwort(e): carcinoma in situ ; chemotherapy ; testicular cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Approximately 5% of patients with testicular cancerharbour carcinoma in situ (CIS) in the contralateral testis. CIS willprogress into invasive tumour in about 50% of cases within fiveyears. The present study evaluated the effect of platinum containingchemotherapy on CIS. Patients and methods: Thirty-three patients with disseminated germ-cellcancer and biopsy proven CIS of the testis were evaluated. Results: CIS had disappeared in the first follow-up biopsy in 30patients. Six patients had a relapse of CIS with or without invasive cancerafter 30, 31, 47, 51, 76 and 95 months from start of chemotherapy. Tworelapses were among six patients who initially received cisplatin,vinblastine and bleomycine and four among 27 patients who initially receivedcisplatin, etoposide and bleomycine. The estimated cumulative risk of CIS five and 10 years after chemotherapywas 21% and 42%, respectively. The estimated cumulativeincidence of spermatogenesis was 64% and 81% at five and 10years of follow-up, respectively. Conclusion: Platinum containing chemotherapy may eradicate CIS. However,patients with CIS may develop invasive cancer in spite of chemotherapy. In thelight of the present data, we recommend radiotherapy to the affected testiclein patients with CIS in the contralateral testis and in patients withbilateral testicular CIS. In patients with extragonadal disease and CIS in onetesticle, orchiectomy of the affected testicle is recommended. In patients forwhom future fertility is an important issue, follow-up including repeatedbiopsies can be offered for a period of at least 10 years.
    Materialart: Digitale Medien
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  • 17
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 9 (1998), S. 967-971 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; colorectal neoplasms ; liver metastasis ; surgery
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 18
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; mediastinum ; non-Hodgkin's lymphoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: To evaluate the clinical features of presentation and the response to two different third-generation regimens (F-MACHOP and MACOP-B) of primary mediastinal large B-cell lymphoma (MLBCL), a recently defined distinct clinicopathological entity of non-Hodgkin's lymphoma (NHL). Patients and methods: Thirty-seven consecutive patients with MLBCL, eight male and 29 female (F/M ratio 1 : 3.5) with a median age of 35 years, were enrolled in the present study. Thirty-five (94.5%) patients presented disease confined to thorax,with chest symptoms of a rapidly enlarging mass in the mediastinum in 70% and superior vena cava syndrome (SCVS) in 43% of these patients. The first 10 patients received F-MACHOP and the succeeding 27 patients MACOP-B chemotherapy, associated in 24 (88.8%) with involved field radiation therapy (IFRT). 67Gallium scan was routinely performed pre- and post-IFRT in 18 patients. Results: All 37 patients were assessable for response: 10 of 10 (100%) in the F-MACHOP and 26 of 27 (96.3%) in the MACOP-B group achieved overall responses (CR+PR). Three of 24 (12.5%) patients in PR after chemotherapy obtained CR after IFRT. Persistent Gallium avidity was observed in 16 patients after chemotherapy and in only four patients after IFRT. Thus far, four of the 10 F-MACHOP and two of the 26 MACOP-B responders have presented disease progression. The probability of progression-free survival (PFS) was 91% and 60% (P 〈 0.02) while overall survival (OS) was 93% and 70% (P = n.s.) at a mean follow-up of 27 and 52 months in the MACOP-B+IFRT and F-MACHOP groups, respectively. Conclusion: MACOP-B+IFRT has proved to be a highly effective and less toxic therapeutic approach for primary MLBCL and appears to be superior to other third-generation chemotherapy regimens.
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  • 19
    ISSN: 1569-8041
    Schlagwort(e): AIDS ; chemotherapy ; G-CSF ; HIV-1 viral replication ; non-Hodgkin's lymphoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: The optimal treatment of AIDS-related NHL (ARL) has yet to be defined. The purpose of this study was 1) to evaluate the efficacy and toxicity of the CNOP-regimen (cyclophosphamide, mitoxantrone, vincristine, and prednison) in combination with G-CSF; and 2) to study the effect of this regimen on HIV-1 viral replication. Patients and methods: A phase II study was performed in 21 previously untreated patients with ARL. Results: Based on intention to treat, the response rate was 43%: four complete and five partial remissions. Median survival was only five months. Only one patient had an opportunistic infection during treatment; three patients had localized infections and one episode of septicaemia was seen. Remarkably, during treatment, in 94% of cases p24 antigen levels either remained undetectable or showed a substantial decrease, even though antiretroviral therapy had been discontinued just prior to the first cycle of chemotherapy in all patients. HIV-1 RNA load decreased or remained unchanged in 82% of patients and increased in three patients. Conclusions: Our data demonstrate, 1) that the CNOP-regimen in combination with G-CSF, although associated with a low risk of both opportunistic and bacterial infections, can not be recommended in the treatment of ARL; but 2) that G-CSF can be used safely to sustain haematopoiesis in patients with ARL treated with chemotherapy.
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  • 20
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; famciclovir ; hepatitis B virus ; lamivudine ; non-Hodgkin's lymphoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Chronic carriers of Hepatitis B virus (HBV) infection, who are treated for malignant lymphoma, are at high risk of mortality from reactivated HBV infection. We report a case of a 29-year-old male chronic HBV carrier who developed fulminant reactivated HBV infection following intensive chemotherapy for stage IVB large cell B-cell non-Hodgkin's lymphoma associated with extensive central nervous system and bone marrow involvement. Prior to chemotherapy the patient had normal liver function tests and was negative for HBV DNA by semi-quantitative PCR assay. Fulminant HBV reactivation was confirmed following clinical deterioration, massive rises in hepatic transaminases (peak alanine aminotransferase = 2,850 U/l), liver biopsy and rising levels of serum HBV DNA. Following treatment with lamivudine 150 mg bd for 18 weeks dramatic and sustained recovery ensued. Symptoms and liver function tests improved within days and HBV DNA became negative within 12 weeks. Our patient later died from relapsed lymphoma but without evidence of reactivated HBV infection. We advise that lamivudine should be considered during intensive chemotherapy treatment of chronic carriers of HBV.
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  • 21
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; non-small-cell lung cancer ; paclitaxel ; vinorelbine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: We designed a phase I–II trial of three active agents,paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lungcancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximumtolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2)determine the overall response rate and median survival of patients treatedon this regimen. Patients and methods: We treated cohorts of patients with stage IIIB orIV NSCLC with ifosfamide 1.2–1.6 g/m2/day × 3 andvinorelbine 20–25 mg/m2/day × 3 and escalatingdoses of paclitaxel at 100–175 mg/m2 on day 2 with G-CSFsupport on a 21-day cycle. One prior experimental single-agent chemotherapyregimen was allowed. Results: Fifty-six patients, were enrolled on this trial: 27 on the phaseI portion of the study and an additional 29 at the recommended phase II dose(RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel dosesof 175 mg/m2 and 150 mg/m2 produceddose-limiting myelosuppression, and the RPTD was determined to be paclitaxel135 mg/m2 with ifosfamide 1.2 g/m2/day on days1–3 and vinorelbine 20 mg/m2/day on days 1–3 withG-CSF support. The overall response rate was 18%, with a mediansurvival of 6.1 months. Six of 35 patients (17%) treated at the RPTDachieved a partial response to therapy. Grade IV neutropenia was observed in19 of 35 patients at this dose, with eight patients suffering febrileneutropenia. Conclusions: This non-cisplatin-containing three-drug regimen hassubstantial toxicity and low activity in advanced NSCLC, and does not seem toimprove on prior regimens. It is unclear whether the lack of efficacy relatesto an antagonistic reaction between the specific drugs, administrationschedule, or to subtherapeutic doses of the individual agents.
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  • 22
    ISSN: 1436-2813
    Schlagwort(e): Key Words: non-Hodgkin's lymphoma ; mesenterium ; intraoperative radiation therapy ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: also been consistently associated with a poorer response rate and a shortened survival, due to the fact that tumor size is the most significant factor for the treatment of non-Hodgkin's lymphoma. We herein describe a case of a 53-year-old woman presenting with the chief complaint of abdominal fullness, who underwent intraoperative radiation therapy (IORT) for recurrent bulky non-Hodgkin's lymphoma in the mesenterium. The patient has had no evidence of tumor recurrence, based on the findings of regular abdominal computed tomographic scans, 60 months after initial chemotherapy and 28 months after IORT.
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  • 23
    ISSN: 1436-2813
    Schlagwort(e): Key Words: liver micrometastasis ; chemotherapy ; portal vein ; hepatic artery ; bromodeoxyuridine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 24
    ISSN: 1436-2813
    Schlagwort(e): Key Words: advanced gallbladder cancer ; adoptive immunotherapy ; chemotherapy ; tumor-infiltrating lymphocytes ; cytotoxic T lymphocytes
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 25
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; mesothelioma ; symptom relief
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: To evaluate the therapeutic impact of a simple combination chemotherapy regimen on symptoms related to malignant mesothelioma. Materials and methods: Between October 1986 and June 1997, 39 patients with advanced inoperable malignant mesothelioma were treated with palliative MVP (mitomycin-C 8 mg/m2 q. six weeks, vinblastine 6 mg/m2 q. three weeks and cisplatin 50 mg/m2 q. three weeks) chemotherapy and assessed for objective response and relief of symptoms. Results: Eight of 39 patients (20%) achieved an objective partial response with a median duration of nine months: only five patients had progression of disease during chemotherapy. Twenty-four of 39 (62%) had an overall improvement in their symptomology with particularly good responses for pain (79%). These benefits were independent of performance status. Resolution of symptoms was achieved in all responding patients within two treatment cycles. There was no statistically significant difference in duration and incidence of symptom response in those patients achieving radiological PR compared with those with no change and more than 60% of patients with radiological no change obtained useful symptom control. The treatment was well tolerated with only four patients developing grade 3 leucopenia and three with grade 3 nausea. Conclusions: MVP is a well tolerated regimen and its use in malignant mesothelioma provides useful symptomatic benefit. These results should be the basis for further trials of MVP in the management of mesothelioma with symptom control as a principal endpoint.
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  • 26
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; cisplatin ; docetaxel ; non-small-cell lung cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: To evaluate the efficacy and safety of the docetaxel-cisplatin combination in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Chemotherapy-naïve patients with histologically confirmed, measurable stage IIIB or IV NSCLC, a World Health Organization (WHO) performance status of 0–2 and adequate bone marrow, renal, hepatic and cardiac function were eligible for the study. Patients received docetaxel (100 mg/m2) as an one-hour infusion on day 1 and cisplatin (80 mg/m2) as a 30-min infusion with appropriate hydration on day 2. Granulocyte colony-stimulating factor (G-CSF; 150 µg/m2 , SC) was given on days 3 to 13. Treatment was repeated every three weeks. Results: Fifty-three patients were enrolled (28 with stage IIIB and 25 with stage IV). One complete and 23 partial responses were observed (overall response rate (OR): 45%; 95% CI: 34.1%–61.8%). The response rate was 57% and 32% in patients with stages IIIB and IV disease (P = NS). The median time to progression was 36 weeks and the median survival 48 weeks; the one-year survival was 48%. Grade 3–4 neutropenia occurred in 23 patients, 15 of whom were hospitalized for neutropenic fever; two patients died of sepsis. Grade 2 neurotoxicity was observed in six patients and grade 3 in five patients; grade 3 fatigue occurred in seven patients, grade 3–4 mucositis in four patients and grade 3–4 diarrhea in six patients. Mild allergic reactions and oedema were observed in five and four patients, respectively. The median dose intensity was 30 mg/m2 /week for docetaxel and 24 mg/m2 /week for cisplatin, corresponding to 91% and 89% of the specified protocol doses, respectively. Conclusions: The docetaxel–cisplatin combination is an active regimen in advanced NSCLC, but hematologic toxicity remains high despite the prophylactic use of G-CSF.
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  • 27
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 9 (1998), S. 63-65 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; combined modality treatment ; early stages ; Hodgkin's disease ; induced tumours ; late toxicity ; radiotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract For decades, radiotherapy has been used as a single treatment modality for early stage Hodgkin's disease. In recent years, late radiation effects, such as myocardial infarctions and induced solid tumours, have become of major concern. It now seems clear that chemotherapy coupled with radiotherapy not only improves relapse-free survival, but can also replace radiotherapy as adjuvant treatment for subclinical disease. This offers the opportunity of reduction of extended fields and high doses, which hopefully correlates with lower late radiation toxicity. The challenge for clinical trials on the treatment of early stages Hodgkin's disease in the coming years will be the trade-off between adjuvant radiotherapy and adjuvant chemotherapy, reducing radiotherapy in volume and dose without jeopardising the 90% overall survival that can be achieved nowadays.
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  • 28
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 9 (1998), S. 57-62 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; chemotherapy-radiotherapy combination ; Hodgkin's disease ; limited stages ; radiotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract For limited stage Hodgkin's disease (HD), the role of radiotherapy has been changing during the last decades, the main point being the (almost) complete disappearance of irradiation used alone. Actually, exclusive radiotherapy yielded satisfactory results in terms of long-term survival, but in 1998, it was becoming impossible not to take into account the late overmortality observed in all large cohorts of HD patients. This overmortality has been shown to be related (1) to cardiac toxicity of irradiation and (2) to secondary radiation-induced solid tumors. So the search for new strategies, as efficient, but less toxic, could not be avoided any more. For surgically staged patients (pathological stages I and II), irradiation alone (i.e., mantle field radiotherapy) can still be proposed to patients without unfavourable prognostic factors after a negative surgical infra-diaphragmatic exploration. For clinically staged patients with limited disease and favourable prognostic indicators, the association of chemotherapy and radiotherapy appears more and more as a standard. In parallel, efforts are being made to alleviate the therapeutic burden. For radiotherapy, previous experience showed that, after a chemotherapy-induced complete remission, irradiation of the initially involved areas only was enough treatment. Ongoing trials are now exploring the possibility of a dose desescalation from the conventional 36 Gy to 20 Gy (as for children HD), and maybe to ... 0 Gy (no radiotherapy at all). Desescalation in the number of chemotherapy cycles is also being investigated. For clinically staged patients with unfavourable prognostic indicators, a higher percentage of cases still appears to be refractory to treatment. So, while chemo-radiotherapy clearly became the standard strategy, efforts are essentially being devoted to identify new - and hopefully more efficient - chemotherapy schemes. In parallel, irradiation dose desescalation is being investigated. Most of these pending questions are addressed in a number of ongoing trials, as well in the US as in Europe, with the aim of offering to patients treatments at least as efficient as the presently used schedules, and less toxic in the long term.
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  • 29
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 9 (1998), S. 73-78 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; dose response relationship ; Hodgkin's disease ; randomised clinical trials ; statistical models ; tumour growth kinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract In this article we summarize the theoretical arguments which led us in the German Hodgkin's Disease Study Group to introduce the BEACOPP-regimen and to initiate a large randomised trial to investigate the role of moderate dose escalation in the treatment of advanced stage Hodgkin's disease. Although some indications for a role of dose were available in the early 1990s no prospective randomised trial had been undertaken. In order to obtain an impression of the shape of the essential dose response characteristic we developed a novel statistical model that could be used to analyse a set of data in which dose variations had occured. The model took tumour growth and chemotherapy effects into account. The model could be applied to clinical data on tumour control and treatment given in a patient population. The model was fitted to the data of 706 patients which had received COPP/ABVD-like regimens. It revealed considerable heterogeneity in chemosensitivity and a positive slope of the doseresponse relationship. The model was used to simulate the effect of various treatment strategies with dose escalation and schedule changes. On the basis of such simulations we predicted that shortening cycle intervals from 4 to 3 weeks should lead to small benefits (about 3% in five-year tumour control rates). In contrast, we predicted that a moderate average dose escalation by 30% of a standard chemotherapy would lead to a potential benefit in the order of 10%-15% in tumour control at five years. Subsequently we searched for a treatment scheme that would permit such a dose escalation. The BEACOPP-scheme was invented to allow the three major myelotoxic substances (cyclophsphamide, adriamycin and etoposide) to be given in the beginning of a cycle. These three substances were then subject to dose escalation in a dose finding trial. G-CSF was introduced to compensate for the myelotoxic effects. The dose level found feasible for a large multicentre setting turned out to be in the required magnitude. The HD9 trial of the GHSG was then initiated to examine whether the predicted dose response curve really exists.
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  • 30
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; CHOP ; etoposide ; high-grade non-Hodgkin's lymphoma ; risk factors
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Second- and third-generation chemotherapy protocols for the treatment of aggressive non-Hodgkin's lymphomas (NHL) have considerable, and age-related, toxic effects. In addition, they do not seem to prolong overall survival in comparison to standard CHOP chemotherapy. In this phase II study we investigated the feasibility and efficacy of the addition of etoposide to the conventional CHOP regimen. Patients and methods: Toxicity and clinical efficacy were determined in 132 patients with previously untreated high-grade NHL. There were 51 patients in clinical stage I and II and 81 patients in stage III and IV, with a median age of 54 years (range 17–85). Patients received standard-dose CHOP plus etoposide 100 mg/m2 i.v. on day 1 and 200 mg/m2 p.o. on days 2–3. Results: The overall response rate was 84%, with 70% complete and 14% partial responses. The predicted three- and five-year survivals for the group as a whole were 60% and 53%, respectively, and the corresponding disease-free survivals for patients achieving complete remissions were 65% and 56%, respectively. Outcome was not different from that of CHOP-treated patients in a recently completed Nordic study performed during the same time period. Myelosuppression (WHO grade 3–4), observed in 87% of patients and infectious complications (WHO grade 3–4) in 33%, dominated the toxicity profile of this regimen. Fifty-seven of 92 complete responders (62%) received 6–8 CHOP-E cycles with no reductions in planned dose intensity. LDH level higher than normal, extranodal sites = 2, stage III–IV at diagnosis were all indicators of a poor survival. Conclusions: We conclude that CHOP-E treatment is effective in high-grade NHL. However, mainly due to severe myelosuppression frequent schedule modifications were required and the results are not obviously superior to those of conventional CHOP.
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  • 31
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; gemcitabine ; new drugs ; non-small-cell lung cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: The aim of this study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine plus cisplatin, administered every three weeks, in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Twenty-six previously untreated stages III (14) and IV (12) patients were included. Gemcitabine was administered on days 1 and 8 at a dose of 1250 mg/m2 and cisplatin was administered at a dose of 100 mg/m2 on day 1, every 21 days. Results: Twenty-five patients were evaluable for response. One patient achieved a complete response, and 16 patients partial responses. The overall response rate was 65.3% (95% CI: 45%–82%). The main toxicity was hematological: neutropenia NCIC-CTC grade 3–4 in 54% of the patients, and thrombocytopenia grade 3–4 in 23%. The non-hematological toxicity was mild and tolerable. Only 13% of gemcitabine injections were dose-reduced or omitted due to toxicity. The actual dose-intensity of gemcitabine was 715 mg/m2/week, and 31 mg/m2/week for cisplatin. These figures represent the 86% and 93% of the theoretical dose intensity of both drugs, respectively. With a median follow-up of 10 months (range 7–13), 17 patients are still alive and nine have died. The median overall survival is 12 months. Conclusion: This novel combination of gemcitabine and cisplatin administered every three weeks is well tolerated and induces a remarkably high response rate. The regimen proves more interesting than the four-week schedules, particularly regarding patients who are candidates for local therapy.
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  • 32
    ISSN: 1573-0646
    Schlagwort(e): chemotherapy ; camptothecin analogs ; regional drug delivery
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Objective. To determine the maximum tolerated dose and pharmacokinetics of topotecan when administered by the intraperitoneal route. Methods. A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusion over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. Results. Seventeen patients received a total of 43 cycles at 21-day intervals. The maximum tolerated dose was 4 mg/m2 and acute dose-limiting toxicity was neutropenia. Other toxicities included leukopenia, anemia, emesis, fever, and abdominal pain. Although no objective responses were achieved, five of ten patients with ascites had a decrease in fluid accumulation with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m2. Pharmacokinetic analysis performed at a dose of 3 mg/m2 demonstrated that elimination from the peritoneal cavity followed second-order kinetics with k1 = 1.6 hr-1, k2 = 0.3 hr-1 and first and second-phase half-lives of 0.49 and 2.7 hours, respectively. Plasma pharmacokinetic behavior was best described by first-order kinetics with k = 0.5 hr-1 and a half-life of 3.9 hours. The pharmacologic advantage, expressed as the peritoneal to plasma AUC ratio was 31.2. Conclusions. Intraperitoneal administration of topotecan at 3 mg/m2 results in a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure; this may be beneficial for the treatment of patients with ovarian cancer or intraperitoneal carcinomatosis.
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  • 33
    ISSN: 1573-0646
    Schlagwort(e): chemotherapy ; paclitaxel ; continuous infusion ; myelosuppression
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Purpose: Pre-clinical data have suggested that prolonged exposure to paclitaxel enhances its cytotoxicity, but various clinical trials utilizing long-term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitaxel administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated dose for the 10-day infusion duration. Patients and methods: Twenty-nine solid tumor patients (predominantly non-small cell lung cancer and head and neck cancer) were treated with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as a 10-day continuous infusion via a pump every 21 days. Dose escalation was permitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC ≤ 500 or platelet count ≤ 25,000 for ≥ 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients developed DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received standard pre-medications for paclitaxel, including anti-histamines and corticosteroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used. Results: A total of 110 courses of paclitaxel were administered to 29 patients. The incidence of hematologic and non-hematologic toxicity was quite low among the patients treated at dose levels below 17 mg/m2/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue, nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m2/day dose level. Conclusion: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour paclitaxel infusions, dose-reduction for myelosuppression may not be necessary because the MTD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.
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  • 34
    ISSN: 1573-0646
    Schlagwort(e): germ cell tumors ; edatrexate ; chemotherapy ; salvage
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Up to 30% of patients with advanced germ cell tumors will fail induction chemotherapy or will relapse. New agents with activity in this still potentially curable subgroup of patients are needed. Edatrexate (10-ethyl, 10-deaza-aminopterin) is a methotrexate analogue that has preclinical and clinical activity in breast, lung, and head and neck cancers, as well as in non-Hodgkin's lymphomas. A phase II trial of edatrexate in relapsed or refractory malignant germ cell tumors was conducted by the Southwest Oncology Group (SWOG). Twenty-five patients were enrolled in the trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for four weeks followed by a one-week rest period. The treatment course was repeated every five weeks. Among the 23 patients evaluable for response, there were no objective responses with all patients developing progressive disease. Thirteen patients (56%) developed Grade 3–4 toxicities, predominantly stomatitis and malaise/fatigue/lethargy. One patient developed Grade 4 anemia while another developed grade 4 anemia and thrombocytopenia. No patients discontinued treatment due to toxicity nor were there any toxic deaths. Edatrexate administered in this dose and schedule has no antitumor activity and has substantial toxicity in patients with relapsed or refractory germ cell tumors.
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  • 35
    ISSN: 1573-7373
    Schlagwort(e): cisplatin (CDDP) ; methotrexate (MTX) ; C6 glioma ; chemotherapy ; leukotriene C4 (LTC4)
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Previous work in our laboratory has shown a correspondence between the chemosensitivity of C6 rat glioma and that of human glioblastoma (GBM) to a panel of chemotherapeutic agents in vitro, as determined by the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] colorimetric assay. In the present study, an in vivo model of intracerebral C6 glioma in Sprague-Dawley rats was used to determine if a correlation exists between in vitro chemosensitivity and in vivo survival of the animals, and post-mortem histopathological changes in the tumor. Cisplatin (CDDP) and methotrexate (MTX), agents previously shown to demonstrate high and low in vitro cytotoxicity, respectively, against C6, were administered by intra-carotid infusion over the course of two days. In a separate series of animals, LTC4 was administered prior to infusion of CDDP or MTX; LTC4 was used in view of its known, selective, vasogenic effect on the permeability of brain tumor capillaries. It was found that survival of animals treated with CDDP alone was increased, although this did not reach statistical significance; histopathologically, CDDP-treated animals showed significant tumor necrosis. However, in CDDP-treated animals, pre-treatment with LTC4 increased survival to a statistically significant degree. When administered alone, LTC4 (not followed by CDDP) had no effect on either survival or histology. The survival-enhancing effect of CDDP, when combined with LTC4, was probably not due to any cytotoxic effect of LTC4; this is based on our finding that, on the in vitro MTT colorimetric assay, LTC4 showed low cytotoxicity for C6 glioma cells. By contrast with CDDP, MTX – with or without pretreatment with LTC4 – affected neither survival nor tumor histology. With respect to the question of correspondence between the MTT colorimetric in vitro assay and in vivo effect, MTX showed a clear correlation: low cytotoxicity in vitro and poor in vivo response. In the case of CDDP, the correspondence was not clear-cut: there was a high level of in vitro chemosensitivity of the C6 cell line to CDDP as well as post-mortem tumor necrosis, but in vivo testing showed no significant prolongation of survival. However, pre-treatment with LTC4 did significantly extend survival in animals treated with CDDP.
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  • 36
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neuro-oncology 36 (1998), S. 159-165 
    ISSN: 1573-7373
    Schlagwort(e): malignant glioma ; radiotherapy ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Results of altered therapy schedules obtained in postoperative treatment of 294 patients with malignant gliomas over last 20 years are presented. During this period 135 patients received Conventional Irradiation and Chemotherapy (CICH), 61 patients received Conventional Irradiation (CI), 59 patients received Split Course High Fractional Dose Irradiation (SCHFDI), and 39 patients received Twice a Day Accelerated Irradiation (TDAI). Actuarial survival rates at 2, 3 and 5 years were 19%, 7%, 0% respectively for patients treated with CICH, and they were 21%, 10%, 0% for CI group, 24%, 12%, 0% for SCHFDI option and 15%, 8%, 0% for TDAI schedule. According to the Cox proportional hazard model, only age was significant factor in prognosis.
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  • 37
    ISSN: 1573-7373
    Schlagwort(e): gliomas ; intracarotid administration ; chemotherapy ; drug delivery ; toxicity ; neuropathology ; vascular pathology ; blood brain barrier ; carboplatin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract RMP-7 is a bradykinin B2 receptor agonist shown to permeabilize the blood-brain barrier, especially that associated with brain tumors, when administered via both intracarotid and intravenous routes. Both routes of administration are currently being tested in human trials in combination with the chemotherapeutic agent carboplatin as therapy for gliomas. As an essential prerequisite to the initial intracarotid clinical trials, the potential neurotoxicity of intra-arterial administration of RMP-7 (at a high or low dose), alone and in combination with carboplatin, was assessed in anesthetized Red Duroc swine. Five treatment groups were evaluated with each pig receiving a series of alternating, intra-arterial infusions of RMP-7 (or saline) followed by carboplatin (or saline), as follows: (1) vehicle control: saline/saline; (2) carboplatin only control: saline/carboplatin (50 mg total); (3) RMP-7 only control: RMP-7 (750 ng/kg)/saline; (4) low dose combination: RMP-7 (75 ng/kg)/carboplatin (50 mg total); and (5) high dose combination: RMP-7 (750 ng/kg)/carboplatin (50 mg total). For each subject, one of the alternating dosing sequences (above) was repeated four times during a single dosing session which lasted approximately 40 minutes. Assessments during the in-life phase of the study in the pre- and post-treatment periods consisted of heart rate, arterial blood pressure (systolic, diastolic, and mean), blood gases, body weight, general clinical observations (including evaluation for neurological deficit) and clinical pathology (including a comprehensive battery of standard blood coagulation, hematological and serum chemistry tests). In addition, during the time of treatment, heart rate and arterial blood pressure were monitored. The animals were terminated two weeks after dosing and the brain and rete mirabile (distal to site of infusion) were evaluated for gross and histopathological abnormalities. The histopathology analysis included a reader-blinded analysis using low and high power light microscopic examination of both H&E and Kluver-Berrera stained sections through several key cortical and subcortical brain regions. Transient decreases in arterial blood pressure (mean of 10–25 mmHg) were observed in both groups receiving the high dose of RMP-7 (i.e., 750 ng/kg). No other side effects attributable to RMP-7 and/or carboplatin were observed, and clinical observations revealed no evidence of neurologic deficits. Post-mortem examination revealed no evidence of CNS or cerebral vascular pathology attributable to carboplatin and RMP-7. This study demonstrates that intracarotid administration of the maximum tolerated dose of RMP-7 (750 ng/kg) alone, or in combination with carboplatin (50 mg) is not accompanied by any serious adverse effect, apparent cerebrovascular abnormality or neuropathologic consequence and offers further evidence for the safety of this novel therapeutic approach for enhancing delivery of chemotherapeutics to brain tumors.
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  • 38
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neuro-oncology 36 (1998), S. 259-267 
    ISSN: 1573-7373
    Schlagwort(e): rhabdomiosarcoma ; brain ; chemotherapy ; long-term survival
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Cerebral rhabdomyosarcoma is a highly aggressive tumor with poor prognosis affecting children and, rarely, adults. The authors describe the case of a patient treated for primary fronto-parietal embryonal rhabdomyosarcoma with a long survival (30 months after surgery) and no clinical or radiological evidence of recurrence and discuss the chemotherapy applied in this case.
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  • 39
    ISSN: 1573-7373
    Schlagwort(e): brain stem tumors ; gliomas ; chemotherapy ; autologous bone marrow rescue
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose. Diffuse pontine tumors are highly lethal, and there are few long-term survivors with the standard treatment of external beam irradiation. We investigated the effectiveness of high-dose thiotepa and etoposide-based chemotherapy regimens with autologous bone marrow rescue (ABMR) in children with pontine tumors. Patients and methods. Sixteen children with diffuse pontine tumors were treated. Ten had resistant or recurrent tumors. All ten had previously received irradiation; five had also received chemotherapy and one, beta-interferon. Three high-dose chemotherapy regimens were employed. Six patients received three days of thiotepa (300 mg/m2/day) and etoposide (250–500 mg/m2/day) (TE); two received three days of carmustine (BCNU) (200 mg/m2/day divided every 12 hours) followed by TE (BTE); and two received three days of carboplatin (500 mg/m2/day) followed by TE (CTE). Six other patients had newly-diagnosed tumors and had not received any prior treatment. They all received the BTE regimen and subsequently were treated with hyperfractionated irradiation (7200–7800 cGy) beginning approximately six weeks post-ABMR. Results. There were two toxic deaths (13%), both in previously treated patients, due to multiorgan system failure and Candida septicemia in one case each. Median survival of the patients with resistant or recurrent disease was 4.7 months (range 0.1–18.7) from time of ABMR. Median survival of the newly-diagnosed patients was 11.4 months (range 7.6–17.1) from the time of ABMR. Conclusion. High-dose chemotherapy utilizing these regimens followed by ABMR did not appear to prolong survival compared to conventional therapy in these children with pontine tumors. Alternative strategies need to be developed for this highly lethal disease.
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  • 40
    ISSN: 1573-7373
    Schlagwort(e): primary gliomatosis ; astrocytoma ; meningeal neoplasms ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Primary leptomeningeal gliomatosis is rare, and the diffuse form (PLDG) is even more unusual. The following report is an example. A 17 year-old man developed a syndrome characterized by extensive basal and chronic spinal meningitis. Routine biological tests showed elevated levels of CSF proteins, and moderate mononuclear pleocytosis, with no direct evidence of neoplasia, leading to a diagnosis of chronic meningitis. A second meningeal biopsy, guided by MRI and performed in the left frontal region, led to the specific diagnosis of primary diffuse leptomeningeal gliomatosis. Treatment including ventricular and lumbar shunting, a course of cortico-spinal radiation, and three courses of an eight-drug systemic chemotherapy with intrathecal methotrexate lead to complete remission over 15 months. We believe that this is the first report of such a remission in the literature.
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  • 41
    ISSN: 1573-7373
    Schlagwort(e): ependymoma ; chemotherapy ; children ; bone marrow reconstitution
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Recurrent intracranial ependymoma is rarely cured by surgery, radiotherapy, and chemotherapy in conventional doses. This study was designed to determine the toxicity, radiographic response rate and outcome following intensive chemotherapy with ThioTEPA, etoposide, carboplatinum and autologous bone marrow rescue (ABMR) for young children with recurrent central nervous system ependymoma. ThioTEPA 300 mg/m2/day (total 900 mg/m2) and etoposide 250 to 500 mg/m2/day (total 750 to 1500 mg/m2) were administered for three consecutive days with or without the addition of carboplatinum 500 mg/m2/day (total 1500 mg/m2) for an additional three consecutive days, and autologous bone marrow was reinfused 72 hours following chemotherapy. Eligibility criteria required adequate renal, hepatic and pulmonary function, and no tumor infiltration of bone marrow. Fifteen children with recurrent intracranial ependymoma, aged 5 months to 12 years (median 22 months), were treated. Five patients died of treatment related toxicities within 62 days of marrow reinfusion. Eight have expired from progressive disease a median of six months post-ABMR, and one has died from unrelated causes. One child remains alive 25 months post-ABMR, following further disease recurrence. No partial or complete responses were observed. This regimen of high-dose ThioTEPA and etoposide with or without additional carboplatinum with ABMR is not an effective strategy for retrieving heavily pre-treated children with recurrent ependymoma.
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  • 42
    ISSN: 1573-7373
    Schlagwort(e): chemotherapy ; children ; hypothalamus ; infant ; pilocytic astrocytoma ; visual pathway
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Hypothalamic/visual pathway astrocytomas in children are usually quiescent, but certain cases contain aggressive neoplasms that cause progressive neurological and visual deterioration. Radiotherapy is not recommended in young children because of its adverse effects later in life. This report describes the efficacy of a chemotherapeutic regimen. Four young children with hypothalamic/visual pathway astrocytoma, with a mean of 18 months of age at diagnosis, were treated with chemotherapy. Three patients had diencephalic syndrome at the disease's onset. Three patients with pilocytic astrocytoma were histologically verified, and another infant was clinically diagnosed. A combination chemotherapy using cisplatin and vincristine was administered in a total of 8 cycles in 3 children and 4 in one child. One patient who demonstrated renal insufficiency after 4 cycles of this regimen was treated with additional 4 cycles using carboplatin instead of cisplatin. The acute and subacute hematologic and otologic toxicities were mild, and a transient renal insufficiency in a child during chemotherapy improved. After chemotherapy, tumor regression was documented in 3 patients, and the disease was observed to be stable in one patient with an evidence of intratumoral necrosis on MRI. Three patients showed neurological and endocrinological improvements. These results suggest that this regimen is feasible in young children and may be useful as a first-line treatment for hypothalamic/visual pathway astrocytomas, which in turn may allow potentially deleterious irradiation on the maturing brain to be deferred until the disease progresses.
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  • 43
    ISSN: 1573-7373
    Schlagwort(e): malignant glioma ; chemotherapy ; epilepsy ; phenytoin ; carbamazepine ; valproic acid
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Adjuvant chemotherapy after cytoreductive surgery and irradiation plays an increasingly important role in the management of human malignant glioma. Here we have examined the effect of three anticonvulsants most commonly administered to glioma patients, carbamazepine, phenytoin and valproic acid, on the cytotoxic and antiproliferative actions in vitro of several cancer chemotherapy drugs currently evaluated for human gliomas. We find that none of the anticonvulsants reduces glioma cell viability or proliferation or modulates glioma cell clonogenicity at clinically relevant concentrations when administered alone. Therapeutic concentrations of either drug fail to alter the effect of cancer chemotherapy drugs in acute cytotoxicity assays or modified clonogenicity assays. A lack of interactions of anticonvulsants and cytotoxic drugs is also observed when the glioma cells are preexposed to the anticonvulsants for prolonged times, suggesting that chronic exposure to anticonvulsants in vivo may not change intrinsic glioma cell sensitivity to cancer chemotherapy. Thus, changes in hepatic enzyme activity or immunological parameters, but not modulation of intrinsic chemotherapeutic drug sensitivity, may influence the choice of an anticonvulsant for seizure control in glioma patients receiving adjuvant chemotherapy.
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  • 44
    ISSN: 1573-7373
    Schlagwort(e): brain neoplasm ; germ cell tumors ; children ; chemotherapy ; radiotherapy ; markers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: Intracranial αFP and βHCG secreting germ cell tumors have a very poor prognosis with local treatment alone. Because of efficacy of chemotherapy in extracranial forms, we tried in the SFOP (Société Française d'Oncologie Pédiatrique) to treat them with chemotherapeutic treatment exclusively. Patients and methods: Eighteen patients (10 αFP, 2 βHCG, 6 αFP and βHCG secretion) were enrolled from January 1988 to December 1992. After biological diagnosis patients were to receive 6 cycles of chemotherapy (vinblastine – bleomycin – carboplatin or etoposide – carboplatin/ifosfamide – etoposide). After completion of chemotherapy, surgery was to be performed in case of residual tumor. Focal radiation was only to be delivered in case of viable residual tumor. Results: All patients had biological remission and tumor reduction. Fifteen patients were treated according to the protocol by chemotherapy alone (13) or chemotherapy and radiation of residue [2]. Twelve of the 13 non irradiated patients relapsed, 8 in local and/or regional area, 3 in cerebrospinal area and 1 in undeterminated area with mild elevation of markers except in one case. Six patients are alive in second complete remission after chemotherapy and/or surgery and then a consolidation treatment with radiation and/or high dose chemotherapy (5) or craniospinal radiation (1). Three patients received radiation after 2 or 3 cycles of chemotherapy as protocol violations and didn't relapse. Thus, 12 patients out of the 18 patients are alive with a median follow up of 68 months. All but 1 had focal radiation as part of treatment. No toxic death was observed. Conclusion: Although survival rate is noteworthy (66%), these tumors were not curable with this conventional chemotherapy alone and focal radiotherapy should be part of the treatment.
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  • 45
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neuro-oncology 37 (1998), S. 271-284 
    ISSN: 1573-7373
    Schlagwort(e): leptomeningeal metastases ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Leptomeningeal metastases (LM) is a common problem in neuro-oncology occurring in approximately 5% of all patients with cancer. Notwithstanding frequent focal signs and symptoms in LM, LM is a disease affecting the entire neuraxis and therefore staging and treatment need encompass all cerebrospinal fluid (CSF) compartments. Central nervous system (CNS) staging of LM includes contrast enhanced cranial computerized tomography (CE-CT) or magnetic resonance imaging (MR-Gd), contrast enhanced spine magnetic resonance imaging (MR-S) or computerized tomographic myelography (CT-M) and radionuclide CSF flow study (FS). Treatment of LM involves involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with LM and may obviate the need for intra-CSF chemotherapy. At present, intra CSF drug therapy is confined to three chemotherapeutic agents (i.e. methotrexate, cytosine arabinoside and thio-TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Although treatment of LM is palliative with an expected median patient survival of 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with LM.
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  • 46
    ISSN: 1573-7373
    Schlagwort(e): carboplatin ; chemotherapy ; malignant glioma ; surgery ; tamoxifen
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Between April, 1992 and December, 1995, forty consecutive patients with a cerebral malignant glioma (WHO Grade III and IV) were enrolled in a trial consisting in surgery and post-operative administration of radiotherapy (4500–6000 cGy), carboplatin (CBDCA; dose of 450–600 mg/m2), and oral tamoxifen (TAM; at doses of 40, 80 or 120 mg/day). Two patients of the TAM group died in the postoperative period from a pulmonary embolism and myocardial infarction, respectively. The patients (all dosages combined) had a median survival time of 13 months from the time of diagnosis. The 12-month and 24-month survival rates were 52% and 32%, respectively. The median relapse-free survival time was 7 months. Patients treated with higher doses of TAM (80–120 mg/day) demonstrated a longer median survival rate (13 months both) and a longer 12-month survival result (58% and 76%, respectively). Patients who assumed TAM for a period longer than 3 months (group+3) have a higher median survival rate (16 months) and better 12-month and 24-month results (62% and 40%, respectively). Moreover, the median relapse-free survival time was 10 months (versus 6 months in group−3; p=0.0038). However, it is not possible to exclude that patients of group+3 had a slower growing or a stable tumor and were well enough to assume TAM for a longer period. The results observed in the TAM-group have been compared with those of 40 matched controls treated with surgery, radiotherapy and CBDCA. These patients had a median survival time of 9 months (p = 0.04) and the 12-month and 24-month survival rates were 30% and 0%, respectively. The median relapse-free survival time was 4 months (p = 0.0014). These data suggest a potential role for combinational TAM-CBDCA therapy in the post-operative treatment of cerebral malignant gliomas; further clinical phase III trials, especially those with higher dosages of TAM are warranted.
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  • 47
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neuro-oncology 38 (1998), S. 187-192 
    ISSN: 1573-7373
    Schlagwort(e): medulloblastoma ; infant ; meningosis ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The outcome of children less than 3 years of age with medulloblastoma has been poor in comparison to older children. The cure rates were below 30%, and the quality of life for cured children was frequently reduced by a complex syndrome of long-term sequelae including intellectual retardation and growth hormone deficiency. Due to the deleterious side-effects of radiotherapy in very young children chemotherapy has played an important role in this group of patients. Firstly, chemotherapy should improve their survival rate. Secondly, it should allow dose reduction of craniospinal irradiation and a smaller involved field. With the goal of improving quality of life radiotherapy should be delayed or even replaced by postoperative chemotherapy. The EFS of low-risk patients steadily improved and is now as high as at least 50%. Since most patients of this group do not need radiation, treatment-related long-term sequelae are minimal. High-risk patients, by contrast, with metastatic disease or measurable postoperative tumor still have a very disappointing progression-free survival in a range below 30% at 3 to 4 years in all large studies. Therefore prevention and effective therapy of meningosis, as well as a good response to induction chemotherapy, are essential for the outcome. Strategies to increase the efficacy of conventional treatment modalities in high-risk patients are under investigation. Recently, interesting results have been published on high-dose chemotherapy followed by autologous stem cell rescue and intraventricular administration of the alkylating agent mafosfamide.
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  • 48
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neuro-oncology 38 (1998), S. 245-252 
    ISSN: 1573-7373
    Schlagwort(e): leptomeningeal metastasis ; radiotherapy ; chemotherapy ; cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Meningeal metastasis occurs in 3–8% of all cancer patients, producing neurologic morbidity and a high mortality. Diagnosis is best established by the demonstration of malignant cells in the cerebrospinal fluid. However, in patients with known cancer, MR scan with gadolinium may be diagnostic when subarachnoid nodules can be demonstrated in the head or spine. Therapy usually involves radiotherapy to symptomatic sites, often followed by intrathecal chemotherapy. Intrathecal chemotherapy is best delivered by an intraventricular reservoir system but can also be delivered by repeated lumbar puncture. Methotrexate, cytarabine and thiotepa are the most common agents instilled into the subarachnoid space. Their limited efficacy can be explained by their restricted spectrum of antitumor activity. Patients with leptomeningeal metastasis from leukemia, lymphoma or breast cancer tend to respond best and this may, in part, be attributed to the relative sensitivity of these primary tumor types to the agents administered intrathecally. Systemic chemotherapy may prove a more attractive alternative to intrathecal drugs since it can penetrate into bulky disease, reach all areas of the subarachnoid space, and not be restricted by CSF bulk flow. The prognosis for patients with leptomeningeal metastasis is poor, most individuals surviving a median of only about four months. Occasional patients do have prolonged survival and improvement of their neurologic function.
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  • 49
    ISSN: 1573-7373
    Schlagwort(e): medulloblastoma ; adult ; chemotherapy ; etoposide ; carboplatin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Medulloblastoma is a rare tumor in the adult population. Current therapies include surgery and irradiation. Unlike in children, chemotherapy is not commonly used, and its potential has poorly been investigated to date. We report the case of an adult patient with disseminated medulloblastoma and fulminant neurological deterioration, precluding craniospinal irradiation. Emergency chemotherapy consisting of carboplatin (400 mg/m2) and etoposide (500 mg/m2) with intrathecal (i.t.) administration of cytosar and hydrocortisone was initiated. Impressive clinical response was achieved after the first cycle of chemotherapy, with the complete disappearance of the lesions detected by MRI. After 3 courses of chemotherapy, the patient underwent craniospinal irradiation (36 Gy to the entire neuraxis and 54 Gy to the posterior fossa). Two months after surgery, the patient was well, with complete clinical recovery, and a new MRI confirmed the disappearance of the lesions. Given the dramatic efficacy of the etoposide-carboplatin association (combined with i.t. cytosar), this regimen has to be considered in an emergency setting and seems to be a very attractive candidate to be investigated as first line therapy for poor risk medulloblastoma in adults.
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  • 50
    ISSN: 1573-7373
    Schlagwort(e): brainstem tumors ; surgery ; radiation therapy ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Objective: This analysis was performed to examine the outcome of adult and pediatric patients with brainstem tumors. Methods and materials: Forty patients with brainstem glioma were evaluated retrospectively. Included were 24 females and 16 males ranging in age from 3 to 81 years (median, 29.5 years). These patients were treated with various combinations of surgery, chemotherapy, and ratiotherapy (RT). The length of follow-up in survivors ranged from 0.6 to 20 years (median: 3.2 years, mean: 6 years). Survival rates were calculated with the Kaplan Meier method and differences between survival curves were calculated using the log-rank test. Results: The overall 2 and 5-year survival rates were 44% and 34%, respectively. The median survival time was 19 months. The 5-year survival rate was 54% for patients with tumors outside the pons compared to 21% for those with tumors involving the pons (p=0.04). The 5-year survival rate was 59% for patients with exophytic tumors as compared to 23% for those with intrinsic tumors (p=0.05). Patients undergoing subtotal resection had a 5-year survival rate of 53% compared to 28% for those having only a biopsy or no surgical intervention (p=0.04). None of the other potential prognostic or treatment related factors evaluated [patient age, tumor grade, tumor histology, radiotherapy parameters (including BID fractionation, 3-D treatment planning, or the use of doses 〉 55 Gy), or the administration of adjuvant chemotherapy] evaluated were associated with patient survival. Conclusions: Brainstem gliomas generally occur in younger individuals. The survival rates were better for patients with exophytic tumors, those involving sites other than the pons, and tumors amenable to subtotal resection. Improvements in the outcome of patients with brainstem gliomas will require new therapeutic approaches.
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  • 51
    ISSN: 1573-7373
    Schlagwort(e): recurrent glioma ; chemotherapy ; response parameter ; Thallium-201 SPECT
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Combination chemotherapy with procarbazine, CCNU and vincristine (PCV) may be effective in patients with recurrent glioma. Response monitoring is mandatory, but radiological response evaluation is often difficult. We evaluated Thallium-201 (201Tl) SPECT as a response parameter in ten patients treated with intensive PCV chemotherapy for recurrent glioma. 201Tl-SPECT studies showed early changes (decreasing volume and intensity) in nine patients and these changes were more pronounced than radiological findings. 201Tl-SPECT results after completion of chemotherapy seemed to correlate with clininal findings during follow up. We conclude that 201Tl-SPECT may contribute to the assessment of response in patients treated with PCV chemotherapy for recurrent glioma.
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  • 52
    ISSN: 1573-7373
    Schlagwort(e): Taxol ; astrocytoma ; radiosensitization ; radiotherapy ; chemotherapy ; tumor recurrence
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The new anticancer agent Taxol appears to potentiate the effects of radiation on brain tumor cell lines in vitro and was recently evaluated by our group as a radiosensitizer in a phase I study for primary brain tumors. In that study, we administered Taxol as a three-hour IV infusion repeated every week for six weeks and gave daily cranial irradiation concurrently for a total of 6000 rads. We reviewed the charts of the 60 patients who participated in the study, and identified twelve patients who underwent a second surgery after treatment because of progressive symptoms and an enlarging intracranial mass on MRI. Pathologically, each patient showed prominent radionecrosis, and other evidence of accelerated radiation changes (confluent areas of coagulative necrosis, bizarre nuclei, marked thickening and fibrinoid changes in multiple blood vessels). These changes were noted many weeks earlier than would be expected after radiation therapy alone and were independent of age, and tumor histology. We postulate that the accelerated radiation changes may be due to the radiation sensitizing effects of Taxol. We also noted a change of the pattern of tumor recurrence, compared to historic reports, and a dose-necrosis relationship where the resected tumor is formed completely of necrotic tissue in patients who received 150 mg/m2 or higher dose of Taxol. These observations may be of significance for future study design.
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  • 53
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neuro-oncology 40 (1998), S. 39-46 
    ISSN: 1573-7373
    Schlagwort(e): brain neoplasms ; chemotherapy ; leukemia
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract We report two patients with acute myeloid leukemia (AML) following therapy for malignant glioma; one was a young women treated heavily with alkylating agents for glioblastoma and the other a young man treated with high doses of procarbazine, lomustine, and vincristine (PCV) for anaplastic astrocytoma. We found 26 other examples of therapy related leukemia in adult and pediatric brain tumor patients. Including our two, there were 12 patients with malignant glioma; median interval from treatment to diagnosis of AML was 31 months. Nine adult malignant glioma patients all received nitrosoureas, some as the sole form of chemotherapy. No definite cases occurred after radiotherapy alone. Based upon analogy with other cancers, the cumulative dose of chemotherapy, especially alkylating agents, is the major risk factor for development of secondary AML. Agents implicated include carmustine (BCNU), lomustine (CCNU), and procarbazine. Conventional radiotherapy appears not to confer additional risk. Progressive macrocytosis, early dose reductions for thrombocytopenia, and refractory anemia may provide early diagnostic clues. Current glioma therapy is leukemogenic but the number of patients who survive the interval required to induce AML is small; nevertheless, the identification of chemosensitive types of glioma, and subgroups of patients who derive the most benefit from chemotherapy, may result in increasing numbers of patients at risk of long term complications. If regimens such as PCV continue to prove valuable in neuro-oncology the risk of leukemia will require integration into the clinical decision process. A search for more effective therapy with minimal mutagenicity remains critical.
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  • 54
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neuro-oncology 40 (1998), S. 59-65 
    ISSN: 1573-7373
    Schlagwort(e): astroblastoma ; glioma ; pediatrics ; radiotherapy ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Astroblastoma is a rare and controversial tumor about which little is known. We have made the diagnosis in seven patients since 1990 at Memorial Sloan-Kettering Cancer Center. Four patients had astroblastomas with anaplastic features, whereas three patients had tumors which were well-differentiated. All three patients with low grade lesions are alive and recurrence free after surgery alone (mean follow-up 29 months). All four patients with anaplastic astroblastoma were treated with surgery, radiotherapy and chemotherapy. One died of infection during induction chemotherapy. Two others died of tumor progression at 28 and 42 months. Radiographic response to chemotherapy was seen in one patient. The results of our series and other reports suggest that anaplastic histology is a prognostic factor in the setting of astroblastoma. More aggressive treatment is necessary for patients with anaplastic astroblastoma although the precise role of irradiation and chemotherapy cannot be defined at this time.
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  • 55
    Digitale Medien
    Digitale Medien
    Springer
    Pituitary 1 (1998), S. 69-81 
    ISSN: 1573-7403
    Schlagwort(e): pituitary tumours ; malignancy ; metastases ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 56
    ISSN: 1573-7217
    Schlagwort(e): advanced breast cancer ; chemotherapy ; cisplatin ; paclitaxel ; weekly schedule
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: In a previous phase I study we found the MTDs of paclitaxel and cisplatin when given together weekly, with or without G-CSF support, in patients with advanced solid tumors. The present study was conducted to define the toxicity and efficacy of this regimen, when used with G-CSF support, in chemotherapy-naive or pretreated patients with advanced breast cancer, and to compare the antiproliferative activity of paclitaxel-cisplatin and paclitaxel-doxorubicin combinations on two human breast cancer cell lines. Methods: Patients with metastatic breast cancer received weekly paclitaxel (as a 3-hour IV infusion) at the dose of 85 mg/m2 (75 mg/m2 in pretreated women) followed by cisplatin (40 mg/m2) for a minimum of 6 weeks. An additional 6 weekly cycles were delivered in patients showing absence of documented disease progression after the first 6 weeks. After the 12th cycle only patients who had shown a substantial tumor shrinkage received 6 further cycles. G-CSF 5 μg/kg was also given, SC on days 3 to 5 of each week, for the whole duration of chemotherapy. The combination of paclitaxel with cisplatin or doxorubicin was also tested in vitro on two breast cancer cell lines (MCF-7 and MDAMB-231). Results: Forty-three women with metastatic breast cancer entered this trial between June 1995 and January 1997. Twenty-seven patients were previously untreated for their metastatic disease (but 23 had previously received adjuvant chemotherapy). The dominant site of disease involvement was visceral in 23, bone in 13, and soft tissues in 7 patients. Seven complete and 15 partial responses were observed in unpretreated patients, while no complete and 6 partial responses were achieved in the pretreated population. The overall response rate, assessed on an 'intent to treat' basis, was 81% (26% CRs) in patients unpretreated for metastatic disease and 37% in those who had received one or more previous chemotherapy regimens. Eighteen responder patients had previously received anthracyclines either as adjuvant chemotherapy (12) or in the treatment of metastatic disease (6). At a median potential follow-up of 12 (range, 3–21) months, 14/27 unpretreated and 12/16 pretreated patients had shown disease progression. The median time to treatment failure was 13 and 7 months, respectively, in the 2 subgroups. The 1-year survival probability was 95% in unpretreated patients. The treatment showed a moderate toxicity in both subgroups of patients. Both hematological toxicity and peripheral neuropathy occurred more frequently in pretreated patients. Treatment-related deaths did not occur, and severe myelosuppression was observed only in pretreated patients with massive liver involvement. Delays in chemotherapy administration were very uncommon, especially during the first 6 treatment cycles, and the average actually delivered dose intensity exceeded 90% in unpretreated patients. The in vitro data on MCF-7 and MDA-MB-231 human breast cancer cell lines showed that exposure to the combination of cisplatin and paclitaxel produced a tumor cell killing similar to that achievable with equivalent concentrations of doxorubicin and paclitaxel. Conclusions: Weekly paclitaxel and cisplatin with G-CSF support is an active and particularly well tolerated treatment for patients with either unpretreated or pretreated metastatic breast cancer. This approach seems quite effective also in patients relapsing after anthracycline-based adjuvant chemotherapy. In view of the negligible hematological toxicity associated with this regimen, further clinical trials testing the addition of non cross-resistant drugs to this combination should be performed.
    Materialart: Digitale Medien
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  • 57
    ISSN: 1573-7217
    Schlagwort(e): breast cancer ; adjuvant therapy ; endocrine therapy ; chemotherapy ; chemoendocrine therapy ; randomized trial ; estrogen receptors ; menopause
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
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  • 58
    Digitale Medien
    Digitale Medien
    Springer
    Breast cancer research and treatment 52 (1998), S. 65-77 
    ISSN: 1573-7217
    Schlagwort(e): HER-2/neu ; c-erbB-2 ; chemotherapy ; tamoxifen ; drug resistance
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Amplification of the HER-2/neu (c-erbB-2) gene resulting in overexpression of the p185HER-2 growth factor receptor occurs in ~25% of early stage breast cancers. HER- 2/neu has been established as an important independent prognostic factor in early stage breast cancer in large cohorts of patients and in cohorts with very long (30 year) follow-up duration. New data are emerging to suggest that HER-2/neu may be useful not only as a prognostic factor but also as a predictive marker for projecting response to chemotherapeutics, antiestrogens, and therapeutic anti-HER- 2/neu monoclonal antibodies. In this review we highlight recent data on HER-2/neu as a predictive marker of response to breast cancer therapy and discuss the clinical implications of this information. The difficulty in comparing results from different data sets due to the wide variety of reagents and technologies used to detect HER-2/neu amplification/overexpression in clinical specimens is also discussed. Finally, we report results from experimental models of HER-2/neu overexpression which have been used in an effort to understand the relationship between HER- 2/neu and response to chemotherapeutics and antiestrogens in breast cancer.
    Materialart: Digitale Medien
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  • 59
    Digitale Medien
    Digitale Medien
    Springer
    Breast cancer research and treatment 52 (1998), S. 175-184 
    ISSN: 1573-7217
    Schlagwort(e): breast cancer ; insulin-like growth factors (IGFs) ; IGF receptors ; IGF binding proteins ; prognosis ; chemotherapy ; hormone therapy ; radiation therapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract IGF1 and IGF2 are circulating peptide hormones and locally-acting growth factors with both paracrine and autocrine functions. IGF1 and IGF2 signal through a common tyrosine kinase receptor, the insulin- like growth factor 1 receptor (IGF1R), and have mitogenic, cell survival, and insulin-like actions that are essential for embryogenesis, post-natal growth physiology, and breast development. The activities of IGF1 and 2 are tightly-regulated by a network of binding proteins and targeted degradation mechanisms. This complex regulatory system is disrupted in breast cancer, leading to excess IGF1R signaling. Evidence for this statement includes: a) breast cancers are infiltrated with IGF2 expressing stromal cells; b) mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) is mutated in breast cancer, leading to loss of IGF2 degradation; c) IGF1R is overexpressed by malignant breast epithelial cells, and in some cases IGF1R is amplified; and d) complex changes in IGF binding protein expression occur during breast cancer progression which most likely also affect IGF1 and 2 signaling. The clinical importance of these epigenetic and genetic changes has recently been stressed by the finding that IGF1R signaling alters the apoptotic response of breast cancer cells to genotoxic stress and, in addition, IGF1R activation sensitizes cells to estrogen by inducing phosphorylation of the estrogen receptor. As a consequence of these findings, we propose that IGF analysis of breast cancer samples should shift from prognostic studies to an evaluation of IGF ligands, receptors, and binding proteins as resistance/sensitivity markers for radiation, chemotherapy, and endocrine therapy.
    Materialart: Digitale Medien
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  • 60
    Digitale Medien
    Digitale Medien
    Springer
    Journal of assisted reproduction and genetics 15 (1998), S. 469-477 
    ISSN: 1573-7330
    Schlagwort(e): primordial follicles ; chemotherapy ; “protective” hormonal treatment ; cryopreservation ; in vitro maturation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: Anticancer treatment causes ovarian failure. Methods: Some hormones may have a protective effect on the ovary. Cryopreservation (freezing) of oocytes has had very limited success, and therefore, currently its use before chemotherapy is not a feasible option. However, cryopreservation of embryos is possible. Another solution is oocyte donation followed by in vitro fertilization (IVF). Results: Ovarian cortical slices containing primordial follicles have been cryopreserved successfully. To restore fertility, cryopreserved–thawed tissue taken from cancer patients before therapy could be replanted after recovery. The possible risk of malignancy restoration could be eliminated by obtaining unilaminar follicles from cryopreserved–thawed tissue and growing them in vitro, followed by routine IVF. Conclusions: Although women who undergo chemotherapy face limited options for fertility preservation, intensive studies in cryopreservation and in vitro maturation of follicles harbor hope for brighter prospects in the future.
    Materialart: Digitale Medien
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  • 61
    Digitale Medien
    Digitale Medien
    Springer
    Cancer and metastasis reviews 17 (1998), S. 163-168 
    ISSN: 1573-7233
    Schlagwort(e): chemotherapy ; multidrug resistance ; chemosensitization
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The expression of drug efflux mechanisms by cancer cells during chemotherapy leads to multidrug resistance (MDR) and constitutes a major obstacle in the effective treatment of cancer. The most widely characterized drug efflex pump is P-glycoprotein (P-gp) and efforts are being directed towards identifying agents that reverse P-gp mediated drug resistance. PSC-833 is a non-immunosuppressive cyclosporin derivative that potently and specifically inhibits P-gp. The current review focuses on the elucidation of the mechanism of action of PSC-833 as a potential MDR reversing agent, using syngeneic multidrug resistant sublines of MDA435 human breast adenocarcinoma cell line that express increasing levels of P-gp. In vitro experiments indicate that PSC-833 interacts directly with P-gp with high affinity and probably interferes with the ATPase activity of P-gp. Studies in multidrug resistant tumor models confirm P-gp as the in vivo target of PSC-833 and demonstrate the ability of PSC-833 to reverse MDR leukemias and solid tumors in mice. Presently, PSC-833 is being evaluated in the clinic.
    Materialart: Digitale Medien
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  • 62
    Digitale Medien
    Digitale Medien
    Springer
    Cancer and metastasis reviews 17 (1998), S. 211-218 
    ISSN: 1573-7233
    Schlagwort(e): chemotherapy ; drug delivery ; liposomes ; antisense ; gene therapy ; drug resistance
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract In the past, our limited understanding of the processes involved in the initiation and growth of cancer hindered our ability to effectively treat most human malignancies and therapies were often associated with significant toxic side effects as well as re-emergence of disease. The development of drug delivery systems such as liposomes has improved the specificity of various conventional anticancer agents by enhancing drug accumulation in tumors while often decreasing exposure to susceptible healthy tissues. More recently, the identification of a wide range of genes and corresponding protein products that are altered in various human cancers has revealed new molecular targets for cancer therapy that may provide improved selectivity for tumor cells over traditional cytotoxic agents. This review discusses how advances in the sophistication of liposomal delivery systems may open new opportunities for combining novel molecular targeting strategies with pharmacological targeting via liposomes to optimize the therapy of many human malignancies.
    Materialart: Digitale Medien
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  • 63
    Digitale Medien
    Digitale Medien
    Springer
    Journal of hepato-biliary-pancreatic surgery 5 (1998), S. 35-40 
    ISSN: 1436-0691
    Schlagwort(e): Key words: hepatocellular carcinoma ; liver transplantation ; chemoembolization ; chemotherapy ; radiotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract: The results of liver transplantation for advanced hepatocellular carcinoma have been disappointing because of high recurrence rates, leading to low long-term survival; this indication remains controversial in an era of organ shortage. To continue to offer this treatment possibility, efforts were made to reduce recurrence and improve survival. The first approach is to maintain a strict selection policy excluding patients with extraheptic disease. The second approach is to test the efficacy of perioperative adjuvant therapies in patients selected for transplantation. The reasons for recurrence include: (1) undetected preoperative micrometastases, (2) intraoperative dissemination by surgical manipulation, and (3) acceleration of tumor growth by immunosuppression. Preoperative treatment, which may include systemic chemotherapy or arterial chemoembolization, seems necessary to limit tumor progression during the waiting period. Systemic chemotherapy has been tested pre-, intra-, and postoperatively. It is considered essential postoperatively and should be used as soon as possible after surgery (i.e., in the 1st postoperative week). Several teams have performed pilot studies that included rather limited numbers of patients, and the results were compared with those for historic controls. Published results show that chemoembolization creates tumor necrosis in most instances. This is efficient in limiting tumor progression but the effect on recurrence and survival is unknown. All authors who used postoperative chemotherapy reported improved survival over controls, with 50%–60% 3-year survival and up to 50% 5-year survival. However, recent results suggest that late recurrence may occur. Chemotherapy was usually well tolerated, although leukopenia, sometimes severe, was observed in most patients. The use of granulocyte colony-stimulating factor seems useful to overcome this problem. Perioperative adjuvant treatments seem to prolong survival in patients undergoing liver transplantation for advanced hepatocellular carcinoma, but delayed recurrence remains possible. Further studies are necessary; these should ideally be multicentric, prospective, and randomized.
    Materialart: Digitale Medien
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  • 64
    Digitale Medien
    Digitale Medien
    Springer
    Journal of hepato-biliary-pancreatic surgery 5 (1998), S. 138-142 
    ISSN: 1436-0691
    Schlagwort(e): Key words: pancreatic cancer ; pancreatoduodenectomy ; chemotherapy ; tumor staging
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract: Modern surgical therapy of pancreatic cancer has resulted in few long-term survivors. There are several reasons. First, most patients are not diagnosed in an early tumor stage, resulting in a minority of patients undergoing surgical resection. A breakthrough in screening methodology is required until this most major of obstacles can be overcome. Second, inaccurate clinical tumor staging is all that is available for the majority of patients, since most patients are not resected. Imaging techniques used for clinical staging require anatomic verification before clinical staging can be reliable. Then adequate comparison of treatments for patients who never receive anatomical staging can accomplished. Postoperative tumor staging using anatomical methods from intraoperative findings and examination of a surgical specimen require a staging system that is simple and directly correlates with survival. The best staging system can be developed only with international cooperation. An adequate comparison of the results of treatment will then be possible. Two broad treatment areas that are most promising are surgical (extending resections to yield negative surgical margins) and adjuvant protocols (beginning with a variety of radio sensitizing chemotherapeutic agents).
    Materialart: Digitale Medien
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  • 65
    ISSN: 1436-0691
    Schlagwort(e): Key words: pancreatic cancer ; survival ; adjuvant therapy ; chemotherapy ; radiation ; gene therapy ; K-ras ; p53 ; p21WAF-1
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract: Multiple genetic alterations, several of which may be important prognostic markers, characterize the development of cancer in pancreas. We review our findings from previously published studies with regard to molecular alterations associated with survival differences in patients treated with conventional radiation and chemotherapies used as adjuvant or palliative therapy. K-ras-negative patients with pancreas cancer show improved survival with radiation therapy compared to K-ras-positive patients with pancreas cancer. p53 expression is associated with shorter survival when compared to no p53 expression in pancreas cancer patients treated with radiation therapy or chemotherapy. Pancreas cancer patients whose tumors express p21 show significant survival advantages when treated with chemotherapy or radiation therapy. An inverse relationship is observed with respect to p21 and p53 expression and clinical stage. Although stage and surgical resectability remain the most important variables with respect to pancreas cancer survival, these findings suggest promising opportunities for gene therapies designed to enhance p21 expression or restore wild-type K-ras or p53 function in pancreatic tumors.
    Materialart: Digitale Medien
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  • 66
    ISSN: 0006-3525
    Schlagwort(e): folding type-specific secondary structure propensities ; amino acids ; α-helical proteins ; β sheet proteins ; α/β proteins ; α+β proteins ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Folding type-specific secondary structure propensities of 20 naturally occurring amino acids have been derived from α-helical, β-sheet, α/β, and α+β proteins of known structures. These data show that each residue type of amino acids has intrinsic propensities in different regions of secondary structures for different folding types of proteins. Each of the folding types shows markedly different rank ordering, indicating folding type-specific effects on the secondary structure propensities of amino acids. Rigorous statistical tests have been made to validate the folding type-specific effects. It should be noted that α and β proteins have relatively small α-helices and β-strands forming propensities respectively compared with those of α+β and α/β proteins. This may suggest that, with more complex architectures than α and β proteins, α+β and α/β proteins require larger propensities to distinguish from interacting α-helices and β-strands. Our finding of folding type-specific secondary structure propensities suggests that sequence space accessible to each folding type may have differing features. Differing sequence space features might be constrained by topological requirement for each of the folding types. Almost all strong β-sheet forming residues are hydrophobic in character regardless of folding types, thus suggesting the hydrophobicities of side chains as a key determinant of β-sheet structures. In contrast, conformational entropy of side chains is a major determinant of the helical propensities of amino acids, although other interactions such as hydrophobicities and charged interactions cannot be neglected. These results will be helpful to protein design, class-based secondary structure prediction, and protein folding. © 1998 John Wiley & Sons, Inc. Biopoly 45: 35-49, 1998
    Zusätzliches Material: 6 Ill.
    Materialart: Digitale Medien
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  • 67
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 45 (1998), S. 69-83 
    ISSN: 0006-3525
    Schlagwort(e): DNA branched junctions ; branch migration ; superhelical torque ; control of DNA structure ; endonuclease VII ; nanomechanical device ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: DNA branched junctions are analogues of Holliday junction recombination intermediates. Partially mobile junctions contain a limited amount of homology flanking the branch point. A partially mobile DNA branched junction has been incorporated into a synthetic double-stranded circular DNA molecule. The junction is flanked by four homologous nucleotide pairs, so that there are five possible locations for the branch point. Two opposite arms of the branched junction are joined to form the circular molecule, which contains 262 nucleotides to the base of the junction. This molecule represents a system whereby torque applied to the circular molecule can have an impact on the junction, by relocating its branch point. Ligation of the molecule produces two topoisomers; about 87% of the product is a relaxed molecule, and the rest is a molecule with one positive supercoil. The position of the branch point is assayed by cleaving the molecule with endonuclease VII. We find that the major site of the branch point in the relaxed topoisomer is at the maximally extruded position in the relaxed molecule. Upon the addition of ethidium, the major site of the branch point migrates to the minimally extruded position. © 1998 John Wiley & Sons, Inc. Biopoly 45: 69-83, 1998
    Zusätzliches Material: 9 Ill.
    Materialart: Digitale Medien
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  • 68
    ISSN: 0006-3525
    Schlagwort(e): conformation ; aggregation ; κ-carrageenan ; flow field-flow fractionation ; multiangle light scattering ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The relatively novel combination of flow field-flow fractionation (FFF) and multiangle light scattering (MALS) was employed to study a nondegraded κ-carrageenan in different 0.1M salt solutions. The applicability of the technique was tested, and the effects of salt type and salt composition on the molar mass and radius of gyration were studied. A conformational ordering was induced at room temperature by switching the solvent from 0.1M NaCl (coil form) to 0.1M NaI (helix form). An approximate doubling of the average molar mass and an increase in radius of gyration was then observed, in agreement with results obtained previously using size exclusion chromatography-MALS. This increase in size was attributed to conformational ordering and to the formation of double helices. Severe aggregation was observed above 40% CsI in the 0.1M mixed salt solution of CsI and NaI. This was ascribed to the association of helices into large aggregates. For these large associates, having molar masses of several millions, a reversal of the elution order in flow FFF was detected. © 1998 John Wiley & Sons, Inc. Biopoly 45: 85-96 1998
    Zusätzliches Material: 10 Ill.
    Materialart: Digitale Medien
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  • 69
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 45 (1998), S. 119-133 
    ISSN: 0006-3525
    Schlagwort(e): conformations of D-alanyl-D-alanine ; β-lactam ; structural overlay ; AMBER force field ; AM1 ; ab initio ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: In this article a conformational analysis of the D-alanyl-D-alanine dipeptide, both charged and neutral, has been carried out. The preferred conformations were determined by means of ab initio and semiempirical quantum, together with empirical force field calculations. The AMBER* force field and the 6-31 + G** and 6-31G** ab initio levels give rise to a coincident minimum energy structure, which, on the other hand, differs from that determined by AM1, 3-21 + G, and 3-21G. The solvent effect on the different charged and neutral conformations have been considered through the AMSOL semiempirical method. A quantification regarding the structural similarities between the different dipeptide conformations and the ampicillin has been performed. The results show that the best overlay is attained by the minimum structure energy obtained by using the 6-31 + G** methodology, which presents a planar amidic nitrogen. © 1998 John Wiley & Sons, Inc. Biopoly 45: 119-133, 1998
    Zusätzliches Material: 5 Ill.
    Materialart: Digitale Medien
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  • 70
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 45 (1998), S. 157-163 
    ISSN: 0006-3525
    Schlagwort(e): chemical oxidation ; cellulose ; conformational transition ; capillary viscosity ; microcalorimetry ; calcium ions ; gels ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The conformational behavior of different molecular weight fractions of a synthetic C6-oxidized derivative of cellulose were investigated by means of capillary viscometry, CD, and microcalorimetric measurements. Experiments were carried out in the presence of either monovalent or divalent counterions.The experimental data indicated that C6-oxidized cellulose can assume an ordered extended conformation at low ionic strength, induced by the intrachain repulsions of negative charges. This conformation was suggested to be very similar to the fully extended structure of cellulose. In addition to this, upon increasing the ionic strength, a conformational transition of the order-to-disorder type occurred. In fact, the screening of the electrostatic repulsions introduced a number of conformational kinks into the cellulosic backbone, which enabled the polymer to assume a more coiled conformation hence producing less viscous aqueous solutions. © 1998 John Wiley & Sons, Inc. Biopoly 45: 157-163, 1998
    Zusätzliches Material: 6 Ill.
    Materialart: Digitale Medien
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  • 71
    ISSN: 0006-3525
    Schlagwort(e): conformational stability ; biological polyelectrolytes ; enthalpy ; entropy ; conformational transitions ; carrageenan ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: A new method is proposed for the determination of the enthalpy and entropy changes of nonionic origin upon conformational transition of linear biopolyelectrolytes in solution. For all transition midpoints, defined by given temperature and ionic strength, the total free energy change of the system is zero, which means that the nonionic contribution to the free energy change is equal in value and opposite in sign to the polyelectrolytic one. The counterion condensation theory of linear polyelectrolytes provides for the appropriate analytical expression to be used in such calculations. Linear plots of the proper functions of the calculated free energy changes vs the proper functions of temperature allows for the determination of the enthalpic and entropic terms of the nonionic free energy change of transition.The method has been applied to the extensive available data of the ion-induced conformational change of κ-carrageenan, a linear sulfated galactan extracted from seaweeds. The method has proved very successful, with the results showing a remarkable convergency of the enthalpy values for different monovalent counterions. On the other hand, the above approach has made it possible to explain the known effect of counterion specificity on the transition by a small difference in the nonionic entropic contributions. © 1998 John Wiley & Sons, Inc. Biopoly 45: 203-216, 1998
    Zusätzliches Material: 5 Ill.
    Materialart: Digitale Medien
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  • 72
    ISSN: 0006-3525
    Schlagwort(e): uv resonance Raman spectroscopy ; Raman cross section ; hypochromism ; DNA ; deoxynucleoside ; protein ; aromatic amino acid ; virus assembly ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Ultraviolet resonance Raman (UVRR) spectra of H2O and D2O solutions of the nucleoside (dA, dG, dC, dT) and aromatic amino acid (Phe, Trp, Tyr) constituents of DNA viruses have been obtained with laser excitation wavelengths of 257, 244, 238, and 229 nm. Using the 981 cm-1 marker of Na2SO4 as an internal standard, Raman frequencies and scattering cross sections were evaluated for all prominent UVRR bands at each excitation wavelength. The results show that UVRR cross sections of both the nucleosides and amino acids are strongly dependent on excitation wavelength and constitute sensitive and selective probes of the residues. The results provide a library of UVRR marker bands for structural analysis of DNA viruses and other nucleoprotein assemblies. © 1998 John Wiley & Sons, Inc. Biopoly 45: 247-256, 1998
    Zusätzliches Material: 4 Ill.
    Materialart: Digitale Medien
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  • 73
    ISSN: 0006-3525
    Schlagwort(e): hemoglobin ; hexagonal bilayer ; Lumbricus ; electron microscopy ; three-dimensional reconstruction ; small-angle x-ray scattering ; three-dimensional models ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The quaternary structure of Lumbricus terrestris hemoglobin was investigated by small-angle x-ray scattering (SAXS). Based on the SAXS data from several independent experiments, a three-dimensional (3D) consensus model was established to simulate the solution structure of this complex protein at low resolution (about 3 nm) and to yield the particle dimensions. The model is built up from a large number of small spheres of different weights, a result of the two-step procedure used to calculate the SAXS model. It accounts for the arrangement of 12 subunits in a hexagonal bilayer structure and for an additional central unit of cylinder-like shape. This model provides an excellent fit of the experimental scattering curve of the protein up to h = 1 nm-1 and a nearly perfect fit of the experimental distance distribution function p(r) in the whole range. Scattering curves and p(r) functions were also calculated for low-resolution models based on 3D reconstructions obtained by cryoelectron microscopy (EM). The calculated functions of these models also provide a very good fit of the experimental scattering curve (even at h 〉 1 nm-1) and p(r) function, if hydration is taken into account and the original model coordinates are slightly rescaled. The comparison of models reveals that both the SAXS-based and the EM-based model lead to a similar simulation of the protein structure and to similar particle dimensions. The essential differences between the models concern the hexagonal bilayer arrangement (eclipsed in the SAXS model, one layer slightly rotated in the EM model), and the mass distribution, mainly on the surface and in the central part of the protein complex. © John Wiley & Sons, Inc. Biopoly 45: 289-298, 1998
    Zusätzliches Material: 4 Ill.
    Materialart: Digitale Medien
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  • 74
    ISSN: 0006-3525
    Schlagwort(e): conformational changes ; vicinal glycosylation ; branched α-l-Rhap(1-2)[β-d-Galp(1-3)]-β-d-Glc1-OMe trisaccharide ; parent disaccharides ; hydrogen bond ; isotope effect ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Conformations of the α-l-Rhap(1-2)-β-d-Glc1-OMe and β-d-Galp(1-3)-β-d-Glc1-OMe disaccharides and the branched title trisaccharide were examined in DMSO-d6 solution by 1H-nmr. The distance mapping procedure was based on rotating frame nuclear Overhauser effect (NOE) constraints involving C- and O-linked protons, and hydrogen-bond constraints manifested by the splitting of the OH nmr signals for partially deuteriated samples. An “isotopomer-selected NOE” method for the unequivocal identification of mutually hydrogen-bonded hydroxyl groups was suggested. The length of hydrogen bonds thus detected is considered the only one motionally nonaveraged nmr-derived constraint. Molecular mechanics and molecular dynamics methods were used to model the conformational properties of the studied oligosaccharides. Complex conformational search, relying on a regular Φ,Ψ-grid based scanning of the conformational space of the selected glycosidic linkage, combined with simultaneous modeling of different allowed orientations of the pendant groups and the third, neighboring sugar residue, has been carried out. Energy minimizations were performed for each member of the Φ,Ψ grid generated set of conformations. Conformational clustering has been done to group the minimized conformations into families with similar values of glycosidic torsion angles. Several stable syn and anti conformations were found for the 1→2 and 1→3 bonds in the studied disaccharides. Vicinal glycosylation affected strongly the occupancy of conformational states in both branches of the title trisaccharide. The preferred conformational family of the trisaccharide (with average Φ,Ψ values of 38°, 17° for the 1→2 and 48°, 1° for the 1→3 bond, respectively) was shown by nmr to be stabilized by intramolecular hydrogen bonding between the nonbonded Rha and Gal residues. © 1998 John Wiley & Sons, Inc. Biopoly 46: 417-432, 1998
    Zusätzliches Material: 12 Ill.
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  • 75
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 489-492 
    ISSN: 0006-3525
    Schlagwort(e): refractive index increment ; proteins ; solvent ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The refractive index increment of a protein solution is a property not only of the protein, but also of the solvent. This is demonstrated theoretically and confirmed experimentally using analytical interferometry. © 1998 John Wiley & Sons, Inc. Biopoly 46: 489-492, 1998
    Zusätzliches Material: 1 Ill.
    Materialart: Digitale Medien
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  • 76
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 47 (1998), S. 1-1 
    ISSN: 0006-3525
    Schlagwort(e): Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: No abstract.
    Materialart: Digitale Medien
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  • 77
    ISSN: 0006-3525
    Schlagwort(e): hepatitis A ; synthetic peptides ; CD ; liposomes ; computational study ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The present study was undertaken to examine the structural features that may be important to explain the immunogenicity of the (110-121) peptide sequence (FWRGDLVFDFQV) of VP3 capsid protein of hepatitis A virus. A conformational analysis of the preferred conformations by CD and molecular mechanics was carried out. Present results suggest that the interaction with liposomes as biomembrane model induces and stabilizes the amphipathic β-structure of the peptide.To study the contribution of amino acid replacements at the RGD tripeptide as well as the influence of the peptide chain length on peptide conformation, solid-phase peptide synthesis of several peptide analogs was carried out and the peptide conformation was studied using CD spectroscopy. The results show that the RGD sequence is necessary to induce the β-structure in the presence of liposomes. © 1998 John Wiley & Sons, Inc. Biopoly 45: 479-492, 1998
    Zusätzliches Material: 9 Ill.
    Materialart: Digitale Medien
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  • 78
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 31-37 
    ISSN: 0006-3525
    Schlagwort(e): DNA liquid crystals ; DNA fragments ; screened Coulomb interactions ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The critical volume fractions pertaining to the formation of DNA liquid crystals were obtained from polarization microscopy, 31P-nmr, and phase separation experiments. The DNA length (approximately one to two times the persistence length 50 nm), ionic strength, and counterion variety dependencies are reported. The cholesteric-isotropic transition is interpreted in terms of the coexistence equations, which are derived from the solution free energy including orientational entropy and excluded volume effects. With the wormlike chain as reference system, the electrostatic contribution to the free energy is evaluated as a thermodynamic perturbation in the second virial approximation with a Debye-Hückel potential of mean force. The hard core contribution has been evaluated with scaled particle theory and/or a simple generalization of the Carnahan-Starling equation of state for hard spheres. For sufficiently high ionic strengths, the agreement is almost quantitative. At lower amounts of added salt deviations are observed, which are tentatively attributed to counterion screening effects. The contour length dependence agrees with a DNA persistence length 50 nm. © 1998 John Wiley & Sons, Inc. Biopoly 46: 31-37, 1998
    Zusätzliches Material: 4 Ill.
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  • 79
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 245-252 
    ISSN: 0006-3525
    Schlagwort(e): gelatin ; gelation ; atomic force microscopy ; interfacial rheology ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Gelation of gelatin under various conditions has been followed by atomic force microscopy (AFM) with the objective of understanding more fully the structure formed during the gelation process. AFM images were obtained of the structures formed from both the bulk sol and in surface films during the onset of gelation. While gelation occurred in the bulk sol, the extent of helix formation was monitored by measurements of optical rotation, and the molecular aggregation was imaged by AFM. Interfacial gelatin films formed at the air-water interface were also studied. Measurements of surface tension and surface rheology were made periodically and Langmuir-Blodgett films were drawn from the interface to allow AFM imaging of the structure of the interfacial layer as a function of time. Structural studies reveal that at low levels of helical content the gelatin molecules assemble into aggregates containing short segments of dimensions comparable to those expected for gelatin triple helices. With time larger fibrous structures appear whose dimensions suggest that they are bundles of triple helices. As gelation proceeds, the number density of fibers increases at the expense of the smaller aggregates, eventually assembling into a fibrous network. The gel structure appears to be sensitive to the thermal history, and this is particularly important in determining the structure and properties of the interfacial films. © 1998 John Wiley & Sons, Inc. Biopoly 46: 245-252, 1998
    Zusätzliches Material: 7 Ill.
    Materialart: Digitale Medien
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  • 80
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 48 (1998), S. 65-81 
    ISSN: 0006-3525
    Schlagwort(e): nucleotide analogue interference mapping ; phosphorothioate ; group I intron ; interference suppression ; RNA ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: In this review I will outline several chemogenetic approaches used to determine the chemical basis of large ribozyme function and structure. The term chemogenetics was first used to describe site-specific functional group modification experiments in the analysis of DNA-protein interactions. Within the past few years equivalent experiments have been performed on large catalytic RNAs using both single-site substitution and interference mapping techniques with nucleotide analogues. While functional group mutagenesis is an important aspect of a chemogenetic approach, chemical correlates to genetic revertants and suppressors must also be realized for the genetic analogy to be intellectually valid and experimentally useful. Several examples of functional group revertants and suppressors have now been obtained within the Tetrahymena group I ribozyme. These experiments define an ensemble of tertiary hydrogen bonds that have made it possible to construct a detailed model of the ribozyme catalytic core. The model includes a functionally important monovalent metal ion binding site, a wobble-wobble receptor motif for helix-helix packing interactions, and a minor groove triple helix. © 1998 John Wiley & Sons, Inc. Biopoly 48: 65-81, 1998
    Zusätzliches Material: 10 Ill.
    Materialart: Digitale Medien
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  • 81
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 48 (1998), S. 83-96 
    ISSN: 0006-3525
    Schlagwort(e): nucleic acid ; disulfide cross-link ; structure ; dynamics ; stability ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: In this review I discuss straightforward and general methods to modify nucleic acid structure with disulfide cross-links. A motivating factor in developing this chemistry was the notion that disulfide bonds would be excellent tools to probe the structure, dynamics, thermodynamics, folding, and function of DNA and RNA, much in the way that cystine cross-links have been used to study proteins. The chemistry described has been used to synthesize disulfide cross-linked hairpins and duplexes, higher order structures like triplexes, nonground-state conformations, and tRNAs. Since the cross-links form quantitatively by mild air oxidation and do not perturb either secondary or tertiary structure, this modification should prove quite useful for the study of nucleic acids. © 1998 John Wiley & Sons, Inc. Biopoly 48: 83-96, 1998
    Zusätzliches Material: 9 Ill.
    Materialart: Digitale Medien
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  • 82
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 48 (1998), S. 113-135 
    ISSN: 0006-3525
    Schlagwort(e): divalent cations ; magnesium ; RNA ; ion binding ; RNA folding ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Divalent cations, like magnesium, are crucial for the structural integrity and biological activity of RNA. In this article, we present a picture of how magnesium stabilizes a particular folded form of RNA. The overall stabilization of RNA by Mg2+ is given by the free energy of transferring RNA from a reference univalent salt solution to a mixed salt solution. This term has favorable energetic contributions from two distinct modes of binding: diffuse binding and site binding. In diffuse binding, fully hydrated Mg ions interact with the RNA via nonspecific long-range electrostatic interactions. In site binding, dehydrated Mg2+ interacts with anionic ligands specifically arranged by the RNA fold to act as coordinating ligands for the metal ion. Each of these modes has a strong coulombic contribution to binding; however, site binding is also characterized by substantial changes in ion solvation and other nonelectrostatic contributions. We will show how these energetic differences can be exploited to experimentally distinguish between these two classes of ions using analyses of binding polynomials. We survey a number of specific systems in which Mg2+-RNA interactions have been studied. In well-characterized systems such as certain tRNAs and some rRNA fragments these studies show that site-bound ions can play an important role in RNA stability. However, the crucial role of diffusely bound ions is also evident. We emphasize that diffuse binding can only be described rigorously by a model that accounts for long-range electrostatic forces. To fully understand the role of magnesium ions in RNA stability, theoretical models describing electrostatic forces in systems with complicated structures must be developed. © 1999 John Wiley & Sons, Inc. Biopoly 48: 113-135, 1998
    Zusätzliches Material: 11 Ill.
    Materialart: Digitale Medien
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  • 83
    ISSN: 0006-3525
    Schlagwort(e): 1H-nmr ; molecular modeling ; peptaibol ; peptide-lipid interaction ; sodium dodecyl sulfate micelles ; trichorzianin TA VII ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Trichorzianin TA VII, Ac0 U1 A2 A3 U4 J5 Q6 U7 U8 U9 S10 L11 U12 P13 V14 U15 I16 Q17 Q18 Fol19, is a nonadecapeptide member of the peptaibol antibiotics biosynthesized by Trichoderma soil fungi, which is characterized by a high proportion of the α,α-dialkylated amino acids, α-aminoisobutyric acid (Aib, U) and isovaline (Iva, J), an acetylated N-terminus and a C-terminal phenylalaninol (Pheol, Fol). The main interest in such peptides stems from their ability to interact with phospholipid bilayers and form voltage-dependent transmembrane channels in planar lipid bilayers. In order to provide insights into the lipid-peptide interaction promoting the voltage gating, the conformational study of TA VII in the presence of perdeuterated sodium dodecyl sulfate (SDS-d25) micelles has been carried out. 1H sequential assignments have been performed with the use of two-dimensional homo- and -heteronuclear nmr techniques including double quantum filtered correlated spectroscopy, homonuclear Hartmann-Hahn, nuclear Overhauser effect spectroscopy, 1H-13C heteronuclear single quantum correlation, and heteronuclear multiple bond correlation. Conformational parameters, such as 3JNHCαH coupling constants, temperature coefficients of amide protons (Δδ/ΔTNH) and quantitative nuclear Overhauser enhancement data, lead to detailed structural information. Ninety-eight three-dimensional structures consistent with the nmr data were generated from 231 interproton distances and six Φ dihedral angle restraints, using restrained molecular dynamics and energy minimization calculations. The average rms deviation between the 98 refined structures and the energy-minimized average structure is 0.59 Å for the backbone atoms. The structure of trichorzianin TA VII associated with SDS micelles, as determined by these methods, is characterized by two right-handed helical segments involving residues 1-8 and 11-19, linked by a β-turn that leads to an angle about 90°-100° between the two helix axes; residues 18 and 19 at the end of the C-terminal helix exhibit multiple conformations. © 1998 John Wiley & Sons, Inc. Biopoly 46: 75-88, 1998
    Zusätzliches Material: 5 Ill.
    Materialart: Digitale Medien
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  • 84
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 127-143 
    ISSN: 0006-3525
    Schlagwort(e): 9-hydroxyellipticine ; DNA ; CD ; linear dichroism ; resonance light scattering ; intercalation ; drug-drug interactions ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The binding of 9-hydroxyellipticine to calf thymus DNA, poly[d(A-T)]2, and poly-[d(G-C)]2 has been studied in detail by means of CD, linear dichroism, resonance light scattering, and molecular dynamics. The transition moment polarizations of 9-hydroxyelliptiycine were determined in polyvinyl alcohol stretched film. Spectroscopic solution studies of the DNA/drug complex are combined with theoretical CD calculations using the final 50 ps of a series of molecular dynamics simulations as input. The spectroscopic data shows 9-hydroxyellipticine to adopt two main binding modes, one intercalative and the other a stacked binding mode involving the formation of drug oligomers in the DNA major groove. Analysis of the intercalated binding mode in poly[d(A-T)]2 suggests the 9-hydroxyellipticine hydroxyl group lies in the minor groove and hydrogen bonds to water with the pyridine ring protruding into the major groove. The stacked binding mode was examined using resonance light scattering and it was concluded that the drug was forming small oligomer stacks rather than extended aggregates. Reduced linear dichroism measurements suggested a binding geometry that precluded a minor groove binding mode where the plane of the drug makes a 45° angle with the plane of the bases. Thus it was concluded that the drug stacks in the major groove. No obvious differences in the mode of binding of 9-hydroxyellipticine were observed between different DNA sequences; however, the stacked binding mode appeared to be more favorable for calf thymus DNA and poly[d(G-C)]2 than for poly[d(A-T)]2, an observation that could be explained by the slightly greater steric hindrance of the poly[d(A-T)]2 major groove. A strong concentration dependence was observed for the two binding modes where intercalation is favored at very low drug load, with stacking interactions becoming more prominent as the drug concentration is increased. Even at DNA : drug mixing ratios of 70:1 the stacked binding mode was still important for GC-rich DNAs. © 1998 John Wiley & Sons, Inc. Biopoly 46: 127-143, 1998
    Zusätzliches Material: 11 Ill.
    Materialart: Digitale Medien
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  • 85
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 169-179 
    ISSN: 0006-3525
    Schlagwort(e): macromolecular carriers ; drug targeting and delivery ; branched chain synthetic polypeptides ; membrane-synthetic polypeptide interaction ; lipid monolayers/bilayers ; polymer therapeutics ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The surface properties at the air/water interface and the interaction of branched chain polymeric polypeptides with a general formula poly[Lys-(DL-Alam-X1)], where X = Π (AK), Ser (SAK), or Glu (EAK), with phospholipids were investigated. Polylysine derivatives with polycationic (SAK, AK) or amphoteric (EAK) were capable to spread and form stable monomolecular layers. The stability of monolayers at the air/water interface was dependent on the side-chain terminal amino acid residue of polymers and can be described by SAK 〈 AK 〈 EAK order. The area per amino acid residue values calculated from compression isotherms were in the same range as compared to those of linear poly-α-amino acids and proteins. Moreover, these polymers interact with phospholipid monomolecular layers composed of dipalmitoyl phosphatidyl choline (DPPC) or DPPC/PG (PG: phosphatidyl glycerol; 95/5, mol/mol). Data obtained from compression isotherms of phospholipids spread on aqueous polymer solutions at different initial surface pressure indicated that insertion into lipid monolayers for SAK or AK is more pronounced than for EAK. The interaction between branched polypeptides and phospholipid membranes was further investigated using lipid bilayers with DPPC/PG and fluorescent probes located either at the polar surface [1-(4-trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) sodium anilino naphthalene sulfonate (ANS)] or within the hydrophobic core (DPH) of the liposome. Changes in fluorescence intensity and in polarization were observed when TMA-DPH or ANS, but not DPH were used. Comparative data also indicate that all three polymers interact only with the outer surface of the bilayer, but even the most marked penetration of polycationic polypeptide (SAK) did not result in alteration of the ordered state of the alkyl chains in the bilayer. Taken together, data obtained from mono- or bilayer experiments suggest that the interaction between branched polymers and phospholipids are highly dependent on the charge properties (Ser vs Glu) and on the identity (Ser vs Ala) of side-chain terminating amino acids. The binding of polymers to the model membranes could be mainly driven by electrostatic forces, but the significant role of hydrophilic properties in case of SAK cannot be excluded. © 1998 John Wiley & Sons, Inc. Biopoly 46: 169-179, 1998
    Zusätzliches Material: 8 Ill.
    Materialart: Digitale Medien
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  • 86
    ISSN: 0006-3525
    Schlagwort(e): Cα,α-dialkylated glycines ; molecular dynamics ; geometry and conformation ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The relationship between the local backbone conformation and bond angles at Cα of symmetrically substituted Cα,α-dialkylated glycines (Cα,α-dimethylglycine or α-aminoisobutyric acid, Aib; Cα,α-diethylglycine, Deg; Cα,α-di-n-propylglycine, Dpg) has been investigated by molecular dynamics (MD) simulation adopting flat bottom harmonic potentials, instead of the usual harmonic restraints, for the Cα bond angles. The MD simulations show that the Cα bond angles are related to the local backbone conformation, irrespectively of the side-chain length of Aib, Deg, and Dpg residues. Moreover, the N-Cα-C′ (τ) angle is the most sensitive conformational parameter and, in the folded form, is always larger and more flexible than in the extended one. © 1998 John Wiley & Sons, Inc. Biopoly 46: 239-244, 1998
    Zusätzliches Material: 3 Ill.
    Materialart: Digitale Medien
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  • 87
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 319-327 
    ISSN: 0006-3525
    Schlagwort(e): methionine ligation ; parathyroid hormones ; biomimetic ligation ; S-methylation ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: In biological systems, both proteolysis and aminolysis of amide bonds produce activated intermediates through acyl transfer reactions either inter- or intramolecularly. Protein splicing is an illustrative example that proceeds through a series of catalyzed acyl transfer reactions and culminates at an O- or S-acyl intermediate. This intermediate leads to an uncatalyzed acyl migration to form an amide bond in the spliced product. A ligation method mimicking the uncatalyzed final steps in protein splicing has been developed utilizing the acyl transfer amide-bond feature for the blockwise coupling of unprotected, free peptide segments at methionine (Met). The latent thiol moiety of Met can be exploited using homocysteine at the α-amino terminal position of a free peptide for transthioesterification with another free peptide containing an α-thioester to give an S-acyl intermediate. A subsequent, proximity-driven S- to N-acyl migration of this acyl intermediate spontaneously rearranges to form a homocysteinyl amide bond. S-methylation with excess p-nitrobenezensulfonate yields Met at the ligation site. The methionine ligation is selective and orthogonal, and is usually completed within 4 h when performed at slightly basic pH and under strongly reductive conditions. No side reactions due to acylation were observed with any other α-amines of both peptide segments as seen in the synthesis of parathyroid hormone peptides. Furthermore, cyclic peptide can also be obtained through the same strategy by placing both homocysteine at the amino terminus and the thioester at the carboxyl terminus in an unprotected peptide precursor. These biomimetic ligation strategies hold promise for engineering novel peptides and proteins. © 1998 John Wiley & Sons, Inc. Biopoly 46: 319-327, 1998
    Zusätzliches Material: 5 Ill.
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  • 88
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 359-373 
    ISSN: 0006-3525
    Schlagwort(e): boundary element method ; DNA electrophoresis ; electrophoretic mobility of DNA ; free solution electrophoretic mobility of DNA ; ion relaxation, DNA electrophoresis ; modeling electrophoresis of polyions ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Boundary element methods are used to model the free solution electrophoretic mobility of short DNA fragments. The Stern surfaces of the DNA fragments are modeled as plated cylinders that reproduce translational and rotational diffusion constants. The solvent-accessible and ion-accessible surfaces are taken to be coincident with the Stern surface. The mobilities are computed by solving simultaneously the coupled Navier-Stokes, Poisson, and ion-transport equations. The equilibrium electrostatics are treated at the level of the full Poisson-Boltzmann equation and ion relaxation is included. For polyions as highly charged as short DNA fragments, ion relaxation is substantial. At .11 M KCl, the simulated mobilities of a 20 base pair DNA fragment are in excellent agreement with experiment. At .04 M Tris acetate, pH = 8.0, the simulated mobilities are about 10-15% higher than experimental values and this discrepancy is attributed to the relatively large size of the Tris counterion. The length dependence of the mobility at .11 M KCl is also investigated. Earlier mobility studies on lysozyme are reexamined in view of the present findings. In addition to electrophoretic mobilities, the effective polyion charge measured in steady state electrophoresis and its relationship to the preferential interaction parameter γgG is briefly considered. © 1998 John Wiley & Sons, Inc. Biopoly 46: 359-373, 1998
    Zusätzliches Material: 3 Ill.
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  • 89
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 45 (1998), S. 341-346 
    ISSN: 0006-3525
    Schlagwort(e): Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: No abstract.
    Zusätzliches Material: 5 Ill.
    Materialart: Digitale Medien
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  • 90
    ISSN: 0006-3525
    Schlagwort(e): diffusional encounter ; Brownian dynamics ; average Boltzmann factor ; acetylcholinesterase ; Poisson-Boltzmann ; electrostatics ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The utility of the average Boltzmann factor around the active site of an enzyme as the predictor of the electrostatic enhancement of the substrate binding rate is tested on a set of data on wild-type acetylcholinesterase and 18 charge mutants recently obtained by Brownian dynamics simulations. A good correlation between the average Boltzmann factors and the substrate binding rate constants is found. The effects of single charge mutations on both the Boltzmann factor and the substrate binding rate constant are modest, i.e., 〈5 fold increase or decrease. This is consistent with the experimental results of Shafferman et al. but does not support their suggestion that the overall rate of the catalytic reaction is not limited by the diffusional encounter of acetylcholinesterase and its substrate. © 1998 John Wiley & Sons, Inc. Biopoly 45: 355-360, 1998
    Zusätzliches Material: 2 Ill.
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  • 91
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 45 (1998), S. 469-478 
    ISSN: 0006-3525
    Schlagwort(e): molecular dynamics ; hydrated proteins ; crystal structures ; density distributions ; globular proteins ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Using molecular dynamics simulations of fully hydrated proteins and analysis of crystal structures contained in the Protein Data Bank, we develop a transferable set of perpendicular radial distribution functions for water molecules around globular proteins. These universal functions may be used to reconstruct the unique three-dimensional solvent density distribution around every individual protein with a modest error. We discuss potential applications of this solvent treatment in protein x-ray crystallographic refinements and in theoretical modeling. We also present a fast, grid-based algorithm for construction of the perpendicular solvent density distributions. © 1998 John Wiley & Sons, Inc. Biopoly 45: 469-478, 1998
    Zusätzliches Material: 6 Ill.
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  • 92
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 47 (1998), S. 23-29 
    ISSN: 0006-3525
    Schlagwort(e): independently folded polypeptide motifs ; miniproteins ; natural target domains ; BBA motif ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: In this paper we present a redesign strategy for the development of uniquely folded polypeptide motifs of less than 40 residues. These mini proteins are based on natural target domains, including the zinc finger domains (BBA motif) Nomenclature corresponds to the defined elements of secondary structure, beginning at the N-terminus of the peptide. Roman lettering refers to a specific motif while Greek characters correspond to the elements of secondary structure within that motif. and the disulfide-rich snake and scorpion toxins (BBB motif). These motifs are designed to act as the molecular framework for the construction of novel functional polypeptides. We will explore the structural determinants of the folded BBA motif, inspired by the zinc finger peptides, in relation to the redesign process. © 1998 John Wiley & Sons, Inc. Biopoly 47: 23-29, 1998
    Zusätzliches Material: 4 Ill.
    Materialart: Digitale Medien
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  • 93
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 47 (1998), S. 75-81 
    ISSN: 0006-3525
    Schlagwort(e): ion channel ; synthetic peptide ; de novo design ; template-assembled synthetic proteins ; supramolecular assembly ; membrane protein ; planer lipid bilayers ; amphiphilic peptide ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: To create ion channel function by synthetic peptides is a challenge in the de novo design of artificial membrane proteins. Amphiphilic α-helical motifs of ∼ 20 amino acid residues to span lipid bilayers are most often used for the creation of peptide ion channels. Template molecules to tether helical peptides have been employed to obtain more organized pore structures. Approaches to form molecular assembly of peptides in the membranes by hydrogen bonding have been also investigated. We have developed approaches to assemble helices with individual amino acid sequences to construct artificial helical proteins. Using one of these approaches, four helices corresponding to the voltage sensor segments (S4 in repeat I-IV) of the sodium channel were assembled on a peptide template to give a protein having ion channel activity with rectification. © 1998 John Wiley & Sons, Inc. Biopoly 47: 75-81, 1998
    Zusätzliches Material: 5 Ill.
    Materialart: Digitale Medien
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  • 94
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 47 (1998), S. 127-142 
    ISSN: 0006-3525
    Schlagwort(e): collagen mimetics ; triple helix ; peptoid ; template ; biophysics ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Collagen peptidomimetics have been synthesized as an alternative to natural collagen. The incorporation of unnatural residues such as peptoids in the collagen sequences can demonstrate potent and specific biological activity and enhance the biostability against enzymatic degradation. Furthermore, the use of achiral peptoids simplifies synthetic strategies by reducing racemization problems. The peptoid residue N-isobutylglycine (Nleu) has been successfully incorporated into a series of collagen mimetics composed of Gly-Pro-Nleu, Gly-Nleu-Pro, and Gly-Nleu-Nleu. The discovery of template-assembled collagen mimetics and metal binding ability has laid the foundation for new opportunities in the design of novel collagen mimetic complexes. This review summarizes the synthesis and integrated biophysical analyses of the structures of these collagen mimetics. Solid phase segment condensation techniques have been utilized for the synthesis of the single chain and template-assembled analogues. The characterization of the collagen-like structures has been established by temperature-dependent optical rotation measurements, CD, NMR spectroscopy, and molecular modelling simulations. © 1998 John Wiley & Sons, Inc. Biopoly 47: 127-142, 1998
    Zusätzliches Material: 20 Ill.
    Materialart: Digitale Medien
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  • 95
    ISSN: 0006-3525
    Schlagwort(e): non-natural amino acid ; peptide ; squarylium dye ; thin film ; poly(3-methylthiophene) ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: We designed a polypeptide that behaves as a photodevice by using a non-natural amino acid with replacement of an α-hydrogen by a squarylium dye and succeeded in syntheses of the non-natural amino acid derivative containing a squarylium and its peptide with trialanine Ala-Ala-Ala. Strong dye-dye interactions were confirmed by absorption and CD spectra for the peptide in 2,2,2-trifluoroethanol solution and in water suspension. The non-natural amino acid derivative could be deposited onto a PMeT/Au electrode by the micelle disruption method. © 1998 John Wiley & Sons, Inc. Biopoly 47: 179-183, 1998
    Zusätzliches Material: 5 Ill.
    Materialart: Digitale Medien
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  • 96
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 47 (1998), S. 263-263 
    ISSN: 0006-3525
    Schlagwort(e): Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: No abstract.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 97
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 117-126 
    ISSN: 0006-3525
    Schlagwort(e): electrostatically driven Monte Carlo method ; cluster analysis ; global energy minimum ; perturbed conformations ; conformational space ; lowest energy conformations ; polypeptide chain ; melittin, membrane-bound portion ; Empirical Conformational Energy Program for Peptides 3 ; annealing methods ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The electrostatically driven Monte Carlo (EDMC) method has been greatly improved by adding a series of new features, including a procedure for cluster analysis of the accepted conformations. This information is used to guide the search for the global energy minimum. Alternative procedures for generating perturbed conformations to sample the conformational space were also included. These procedures enhance the efficiency of the method by generating a larger number of low-energy conformations.The improved EDMC method has been used to explore the conformational space of a 20-residue polypeptide chain whose sequence corresponds to the membrane-bound portion of melittin. The ECEPP/3 (Empirical Conformational Energy Program for Peptides) algorithm was used to describe the conformational energy of the chain. After an exhaustive search involving 14 independent runs, the lowest energy conformation (LEC) (-91.0 kcal/mol) of the entire study was encountered in four of the runs, while conformations higher in energy by no more than 1.8 kcal/mol were found in the remaining runs with the exception of one of them (run 8). The LEC is identical to the conformation found recently by J. Lee, H.A. Scheraga, and S. Rackovsky [(1998) “Conformational Analysis of the 20-Residue Membrane-Bound Portion of Melittin by Conformational Space Annealing,” Biopolymers, Vol. 46, pp. 103-115] as the lowest energy conformation obtained in their study using the conformational space annealing method. These results suggest that this conformation corresponds to the global energy minimum of the ECEPP/3 potential function for this specific sequence; it also appears to be the conformation of lowest free energy. © 1998 John Wiley & Sons, Inc. Biopoly 46: 117-126, 1998
    Zusätzliches Material: 2 Ill.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 98
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 195-200 
    ISSN: 0006-3525
    Schlagwort(e): Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: No abstract.
    Zusätzliches Material: 3 Ill.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 99
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 201-214 
    ISSN: 0006-3525
    Schlagwort(e): band broadening ; dispersion ; DNA ; gels ; electrophoresis ; fluorescence recovery ; photobleaching ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: We determined quantitatively the band broadening effect during gel electrophoresis by measuring the longitudinal dispersion coefficient Dx, with a fluorescence recovery after photobleaching setup, coupled to an electrophoretic cell. We carried out measurements as a function of the electric field, the average pore size, and the molecular length of DNA fragments. Our results are in good agreement with the predictions of the biased reptation model with fluctuations described by T. A. Duke et al. [(1992) Physics Review Letters, vol. 69, pp. 3260-3263]. This agreement is observed on single-stranded DNA [persistence length ≅ 4 nm; B. Tinland et al. (1997) Macromolecules, vol. 30, pp. 5763-5765] in polyacrylamide gels and on double-stranded DNA (persistence length ≅ 50 nm) in agarose gels, two systems where the ratio between the average pore size and the Kuhn length is larger than 1. © 1998 John Wiley & Sons, Inc. Biopoly 46: 201-214, 1998
    Zusätzliches Material: 12 Ill.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 100
    Digitale Medien
    Digitale Medien
    New York : Wiley-Blackwell
    Biopolymers 46 (1998), S. 403-415 
    ISSN: 0006-3525
    Schlagwort(e): molecular dynamics ; DNA curvature ; DNA flexibility ; TATA box functionality ; TATA box binding protein (TBP) ; TBP recognition ; TBP binding ; TBP transcriptional activation ; Chemistry ; Polymer and Materials Science
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Four 1.5 ns molecular dynamics (MD) simulations were performed on the d(GCTATAAAAGGG) · d(CCCTTTTATAGC) double helix dodecamer bearing the Adenovirus major late promoter TATA element and three iso-composition mutants for which physical and biochemical data are available from the same laboratory. Three of these DNA sequences experimentally induce tight binding with the TATA box binding protein (TBP) and induce high transcription rates; the other DNA sequence induces much lower TBP binding and transcription. The x-ray crystal structures have previously shown that the duplex DNA in DNA-TBP complexes are highly bent. We performed and analyzed MD simulations for these four DNAs, whose experimental structures are not available, in order to address the issue of whether inherent DNA structure and flexibility play a role in establishing these observed preferences. A comparison of the experimental and simulated results demonstrated that DNA duplex sequence-dependent curvature and flexibility play a significant role in TBP recognition, binding, and transcriptional activation. © 1998 John Wiley & Sons, Inc. Biopoly 46: 403-415, 1998
    Zusätzliches Material: 6 Ill.
    Materialart: Digitale Medien
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