Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tauromustine (TCNU) is a newly developed nitrosourea compound. As a result of molecular modification, TCNU is more hydrophilic than BCNU and CCNU. In experimental data there was a high therapeutic index, especially in Walker 256 carcinosarcoma in rats, and in phase I trials antitumor activity was observed in NSCLC (10/33 remissions). There was also activity in melanoma, breast cancer, pleuramesotheliomas and ovarian cancer. To determine the effectiveness, duration of response and toxicity of TCNU the following phase II trial was performed. Patients received 130 mg/m2 TCNU every 35 days orally. Twenty-five patients were treated; 22 were evaluable. The female/male ratio was 18/4, 1 patient was stage III, 21 patients stage IV, the mean age was 62.3 years (range 32-70). Between 1 and 4 courses (mean 1.9) were administered. Histology was as follows: 6 squamous cell, 11 adenocarcinoma, 2 large cell and 3 polymorph cell carcinomas. No objective response (CR + PR) was observed; 6/18 patients had stable disease, 7/18 progression and 5/18 early progression. The median survival time is 4.9 months. The most severe side effect was thrombocytopenia (WHO grade 3 + 4, 4/22 patients). TCNU administered at this dose and schedule does not show substantial antitumor activity in patients with NSCLC. The fact that no objective tumor remission was observed suggests that the true response rate is less than 20% (p less than 0.05). It is improbable that TCNU has a relevant impact on the course of inoperable NSCLC.
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PMID:Chemotherapy with tauromustine in advanced non-small cell lung cancer. A trial of the Phase II Study Group of the Association for Medical Oncology of the German Cancer Society. 216 34

One hundred sixty-nine patients with histologic evidence of disseminated malignant melanoma, including patients with cerebral metastases, were entered into a Phase II study of the nitrosourea fotemustine. The treatment regimen consisted of a 100 mg/m2 1 hour IV infusion every week for 3 consecutive weeks, followed by a 4- to 5-week rest period (induction therapy). In responding or stabilized patients, maintenance therapy consisted of 100 mg/m2 every 3 weeks until the disease progressed. One hundred fifty-three patients were evaluable for response. Three complete responses and 34 partial responses were observed (according to the World Health Organization criteria), leading to an objective response rate of 24.2% (95% confidence interval: 17.4% to 31.0%). Responses were also documented on cerebral (25.0%), visceral (19.2%), or nonvisceral (31.8%) metastatic sites. The median duration of response was 22 weeks (range, 7 to 80 weeks). The objective response rate in previously untreated patients was 30.7% (19 of 62 patients). The main toxicity was hematologic with delayed and reversible leukopenia and/or thrombopenia. The objective response rate observed (especially in untreated patients), the activity on cerebral metastases, and the small amount of extra-hematologic toxicity encountered suggest that fotemustine is an effective drug in disseminated malignant melanoma.
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PMID:Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. 222 83

A total of 70 patients presenting with a disseminated malignant melanoma were entered into a multicentric study of combination chemotherapy using dacarbazine and fotemustine. In all, 63 patients were evaluable, 31.8% of whom had previously received cytotoxic chemotherapy. The protocol consisted of induction treatment with a weekly infusion of 100 mg/m2 fotemustine on days 1 and 8 and a daily infusion of 250 mg/m2 dacarbazine on days 15/18 followed by a 4- to 5-week rest period. Responding and stabilized patients were given maintenance treatment comprising fotemustine (100 mg/m2, day 1) and dacarbazine (250 mg/m2, days 2/5) every 3 weeks. The response rate was 33.3% (9 complete responses (CRs) and 12 partial responses (PRs)) and was outstanding among pretreated patients (34.9%). Responses were also documented in cerebral (28.6%), visceral (23.1%) and nonvisceral (43.3%) metastatic sites. Toxicity was mainly hematologic (22.2%, grade III/IV leukopenia; 20.3%, grade III/IV thrombocytopenia) and was acceptable. These results are encouraging in terms of the antitumor activity against nonvisceral metastases (43.3%) and the percentage of CRs obtained (23.3%), and they confirm the activity of fotemustine in cerebral metastatic sites.
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PMID:Combination chemotherapy of dacarbazine and fotemustine in disseminated malignant melanoma. Experience of the French Study Group. 224 37

In this phase II trial, twenty patients with advanced, measurable melanoma from ECOG institutions were treated with esorubicin 30 mg/m2 iv every three weeks. Doses were escalated or reduced based on nadir counts. The dose limiting toxicity was leukopenia with no significant thrombocytopenia or anemia. Other toxicities were mild. One patient had skin necrosis with extravasation. Two patients with soft tissue disease had partial remissions and were treated with 9 and 17 courses. One patient was stable for 8 courses. No cardiac toxicity was seen in three patients receiving more than 150 mg/m2. The response rate was 10% (90% CI = 2 to 30%). Low level activity was seen, but it is unlikely that this drug has sufficient activity to warrant further development in melanoma.
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PMID:Esorubicin (deoxydoxorubicin) has low grade activity in malignant melanoma. Results of an Eastern Cooperative Oncology Group study (EST 2685). 227 73

Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.
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PMID:Phase I clinical and pharmacological study of merbarone. 229 63

A total of 38 patients with metastatic melanoma received monthly chemotherapy with cisplatin at a dose of 200 mg/m2, per cycle; 14 received 20 mg/m2 cisplatin i.v. on days 1-5 and 24 were given 100 mg/m2 i.v. on days 1 and 8. Objective responses were seen in 2/14 treated on days 1-5 and in 5 of 22 evaluable subjects receiving cisplatin on days 1 and 8, for an overall response rate of 22%. The median survival of all patients was 6 months, with no significant difference observed between the two schedules. Severe neurotoxicity and myelosuppression were more common in patients treated on days 1-5. Two patients treated in this manner were bedridden due to neurotoxicity and four developed grade 4 leukopenia after the first cycle of chemotherapy. Only one patient treated with the divided-dose schedule became leukopenic during the first cycle, and none of the patients were debilitated by neurotoxicity. Thrombocytopenia was statistically more severe. Nausea and vomiting, fatigue, ototoxicity, and paresthesia were seen with equal frequency. Very high doses of cisplatin can be delivered with acceptable toxicity using a divided-dose schedule. As the response rate on this schedule appeared to be comparable with that achieved on the more toxic consecutive 5-day schedule, the former deserves to be tested in diseases known to show a dose response to cisplatin. However, in melanoma, administration of 200 mg/m2 per course did not appear to be associated with a markedly improved response rate, compared with cisplatin alone at "standard" doses.
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PMID:High-dose cisplatin in disseminated melanoma: a comparison of two schedules. 230 98

Patients receiving high-dose chemotherapy (HDC) and autologous bone marrow transplantation (ABMT) may experience life-threatening hemorrhagic myocarditis. The authors investigated whether HDC was associated with an acquired platelet defect. Platelet aggregation and release were evaluated after HDC in ten patients with either metastatic breast carcinoma or melanoma. Platelets underwent shape change and a primary wave of aggregation. High-dose chemotherapy was associated with the inhibition of secondary aggregation of platelets induced by adenosine diphosphate (ADP), arachidonic acid, prostaglandin H2 (PGH2) analog (U44619), and collagen. Although electron microscopic study of the platelets revealed normal morphologic features with an adequate number of dense bodies and alpha-granules, release of adenosine triphosphate (ATP) from dense granules was less than 20% of normal. The acquired platelet defect occurred before development of thrombocytopenia. Aggregation of platelets from normal volunteers was not inhibited by either the addition of the chemotherapeutic agents, chemotherapy metabolites, or the patients' sera. In conclusion, HDC induces an acquired abnormality in platelet secretion and aggregation which may contribute to the development of hemorrhagic complications after ABMT.
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PMID:Platelets acquire a secretion defect after high-dose chemotherapy. 231 53

Twenty-seven patients with disseminated malignant melanoma were treated with combination chemotherapy consisting of bleomycin, actinomycin D, DTIC and vindesine. There were 4 complete responses in patients with pulmonary metastasis, 5 patients had a partial remission, 2 of them had mainly lung lesions. Toxicity consisted mainly of leuco- and thrombocytopenia of short duration and sporadic severe mucositis.
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PMID:Phase II study of bleomycin, actinomycin D, DTIC and vindesine in disseminated malignant melanoma. 242 42

Carbetimer, a low molecular weight polymer derived from ethylene and maleic anhydride, belongs to a class of chemical compounds different from previously available anticancer agents. It has shown moderate antitumor activity against the Madison 109, Lewis lung, colon 26 and M5076 ovarian carcinomas. In the human tumor stem cell assay, antitumor activity was seen against carcinomas of the breast, ovary, lung, colon and kidney. A total of 26 patients with solid tumors were entered into this trial; carbetimer was given on 5 consecutive days as a 1-2-h intravenous infusion. The dose was escalated from 1.08 to 11 g/m2/day. The drug did not induce the usual side-effects of chemotherapy: leukopenia, thrombocytopenia, alopecia and mucositis were minimal or totally absent. Gastrointestinal toxicity was limited to mild to moderate nausea and vomiting; these were observed at all dose levels and required antimetics in only two patients. The major side-effects of carbetimer consisted of hypercalcemia and neurotoxicity. Hypercalcemia was dose- and treatment duration-dependent. The precise mechanism of hypercalcemia is presently under investigation, but remains unclear. Neurotoxicity was observed only after prolonged therapy; two patients, who received cumulative doses higher than 250 g/m2, developed a peripheral neuropathy with paresthesia, decrease in sensory perception and motor weakness. One patient recovered completely; the other patient improved slightly before developing fatal brain metastases. Two patients with malignant melanoma exhibited major antitumor response; both were previously treated; after excellent partial responses to carbetimer, both were operated on and one is presently disease-free 2 1/2 years after completion of therapy with carbetimer. In conclusion, carbetimer is a new compound with an unusual pattern of side-effects and interesting antitumor activity against malignant melanoma. Its antitumor activity is presently being investigated in phase II trials.
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PMID:Phase I clinical trial with carbetimer. 253 92

Seventy-seven patients were treated with oral mitozolomide to assess the activity of this drug in melanoma, lung and ovarian cancer. Partial responses were seen in five of 18 evaluable patients with small cell lung cancer (SCLC) and three of 20 with melanoma. No activity was apparent in non small cell lung or epithelial ovarian cancer. The major toxicity was myelosuppression which necessitated reduction in the initial dosage from 115 to 90 mg/m2. However, even at this dose level, unpredictable WHO grade 4 toxicity occurred in non-pretreated patients. Thrombocytopenia was more common than leucopenia and eight patients required platelet transfusion for spontaneous or tumour-related haemorrhage. Myelotoxicity was considered responsible for two deaths and was a significant contributory factor in a further three. Non-haematological toxicity was minor. Thus, despite demonstrable activity in SCLC and melanoma, unpredictable myelosuppression is likely to preclude further assessment in combination chemotherapy regimes in these tumours.
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PMID:Phase II studies of mitozolomide in melanoma, lung and ovarian cancer. 254 29


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