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)

Thirty-two patients with metastatic melanoma received combination chemotherapy and hormonal therapy. Treatment included Carmustine, Cisplatin, Dacarbazine and Tamoxifen (BCDT). The overall response rate was 47%: five patients had a complete response (16%), 10 patients had a partial response (31%) and two had no response (6%). The median survival for responders was 10 months (range 2-20). The BCDT regimen was equally effective against soft tissue and visceral metastases. Neither survival or response rate was modified by pretreatment with alpha-interferon (alpha-IFN). In agreement with the results of a recent randomized trial comparing the efficacy of Dacarbazine with that of Dacarbazine plus Tamoxifen, a better survival was found in women than in men: although the response rate was identical (47%), the median duration of response was higher for women. A fall in serum soluble IL-2 receptor (sIL-2R) levels after therapy was seen in responding patients, confirming the usefulness of this parameter in monitoring disease evolution.
Melanoma Res 1993 Apr
PMID:Therapy for metastatic melanoma: effective combination of dacarbazine, carmustine, cisplatin and tamoxifen. 851 51

O6-Methyl-2'-deoxyguanosine (O6-MedG), a novel inhibitor of O6-alkylguanine-DNA alkyltransferase (O6-AGT), has been synthesized. The ability of O6-MedG to deplete the O6-AGT activity in leukemia L1210 and melanoma B16 cells in vivo has been studied. After intraperitoneal administration of O6-MedG to mice bearing leukemia L1210 or melanoma B16, the activity of O6-AGT in tumour cells decreased by 50%. Pretreatment of leukemia L1210 bearing mice with O6-MedG (200 mg/kg) 24 hours prior to ACNU (15 mg/kg) administration resulted in six out of seven 60-day survivors. Treatment of mice with ACNU (15 mg/kg) alone increased the life span by 200%. Treatment of melanoma B16 bearing mice with O6-MedG and 3 hours thereafter with ACNU resulted in a 50% inhibition of tumour growth, whereas the inhibiting effect of ACNU alone was 16%. There was no difference in leukemia growth when L1210/BCNU bearing mice were treated with O6-MedG followed by ACNU treatment. In vivo ACNU (15 mg/kg) produced a deep and prolonged inhibition of DNA, RNA and protein synthesis in leukemia L1210 cells. The DNA synthesis in leukemia L1210/BCNU cells was shown to recover more rapidly than in L1210 cells. The activities of DNA-polymerases alpha and beta and, especially, of O6-AGT were elevated in ACNU-resistant leukemia cells as compared with ACNU-sensitive cells. The activation of some repairing enzymes, such as O6-AGT, DNA-polymerases alpha and beta as well as increased levels of GSH may play a role in the development of drug resistance to ACNU.
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PMID:[Modulation of the antitumor activity of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosoure a by O(6)-methyl-2'-deoxyguanosine--a new inhibitor of O(6)-alkylguanine-DNA-alkyltransferase]. 856 57

We have analysed the chemosensitivity of 121 human melanoma metastases in the 6-day mouse subrenal capsule assay (SRCA). A total of 13 different chemotherapy regimens were analysed in four successive series. By the original criteria of the assay, 75% of tumours were sensitive to at least one regimen. The most effective combinations, giving sensitivity rates > 40%, were of dacarbazine, vincristine, and BCNU (DOB) with or without metronidazole, followed by cisplatin plus etoposide (Plat-VP16) combined with interferon. On the basis of the SRCA screening we developed a four-drug chemotherapy regimen combined with interferon for metastatic melanoma. Retrospectively analysed the assay correctly identified 77% of clinical responders and 54% of clinical non-responders. The overall predictive accuracy was 65%. Despite the limitations of the assay, it can be used for screening new drugs or combinations.
Melanoma Res 1996 Jun
PMID:Chemosensitivity of human melanoma metastases in mouse subrenal capsule assay--can it predict tumour response to combined cytostatic plus interferon therapy in metastatic melanoma? 881 24

Cisplatin resistance was developed in the human melanoma cell line RPMI8322 by repeated short-term exposures to cisplatin. The most resistant daughter cell line, RPMI8322/CDDP-300, was 4-fold resistant to cisplatin, and partially cross-resistant to carboplatin, melphalan and UV, but not to BCNU. RPMI8322/CDDP-300 cells showed less apoptosis after cisplatin than the parental cells. The cisplatin resistance was not paralleled by a similar reduction in cellular cisplatin accumulation or DNA cross-links in RPMI8322/CDDP-300 cells, and these cells exhibited no increase in cellular glutathione or in mRNA encoding the DNA excision repair protein ERCC1 and XPB. Induction of c-jun mRNA by cisplatin was considerably lower in RPMI8322/CDDP-300 cells than in RPMI8322 cells, consistent with the possibility that c-jun induction may be involved in a pathway that triggers apoptosis after exposure to DNA damaging agents. However, c-jun induction is not necessary for apoptosis, since cisplatin also induced apoptosis in A14 rat embryo fibroblasts, cells in which the c-jun gene is deleted.
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PMID:Apoptosis and c-jun induction by cisplatin in a human melanoma cell line and a drug-resistant daughter cell line. 884 76

The treatment of patients with advanced stage (stage III and IV) melanoma remains discouraging. Except for the study using tamoxifen, combination chemotherapy (cisplatin, DTIC, BCNU), plus biological therapy (IFN-alpha and/or IL-2), which achieved a 57% response rate, virtually any combination of agents or modalities yielded response rates of only 20% to 30%, and none are effective in central nervous system metastases. Durable clinical cures in patients with advanced-stage disease are extremely rare and can probably be attributed more to host defense mechanisms than iatrogenic intervention. The future in treatment then can only look promising to immunologists, molecular biologists, and clinicians striving to elucidate the biological mechanisms isolated patients have for destroying melanoma cells and incorporating those mechanisms into therapeutics for the remainder of melanoma victims.
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PMID:Melanoma: epidemiology, pathogenesis, and new modes of treatment. 890 99

Local chemotherapy with biodegradable polymers prolongs survival with minimal morbidity in patients with intracranial high-grade gliomas. However, use of local chemotherapy for metastatic brain tumors has not been defined. We studied the safety and the efficacy of locally delivered chemotherapy with and without concurrent radiation therapy in treating tumors that frequently metastasize to the brain. The chemotherapeutic agents 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), carboplatin, and camptothecin were incorporated into controlled-release polymers and tested individually against intracranial challenges with one of four tumors (lung carcinoma, renal cell carcinoma, colon carcinoma, and melanoma). For each combination of drug and tumor type, four groups were tested: (a) empty polymer (no drug); (b) external beam radiotherapy (XRT) alone; (c) local chemotherapy from biodegradable polymer alone; and (d) local chemotherapy and XRT together. Polymers were implanted 5 days after tumor inoculation; XRT was given on days 7-9 (300 cGy/day). BCNU and XRT together were effective against all four tumors. BCNU polymer alone significantly prolonged survival in mice with intracranial melanoma or renal cell carcinoma. Carboplatin alone was effective against both melanoma and colon carcinoma and in combination with XRT against colon and renal cell carcinomas. Camptothecin was effective only with XRT against melanoma. These studies demonstrate that local delivery of chemotherapy with concurrent radiation therapy is safe and can significantly prolong survival in models of common intracranial metastatic tumors. Concurrent use of local chemotherapy with standard XRT appears to be more effective than either treatment alone. Local chemotherapy may also be of benefit to patients who have previously received maximal cranial irradiation but suffer an intracranial recurrence.
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PMID:Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. 891 60

Melanoma is rare in Singapore with an age-standardised rate (ASR) of 0.4-0.8 per 100,000 per year. Thirteen patients with metastatic or locally advanced melanoma were referred to the Department of Medical Oncology, Singapore General Hospital between Feb 1991 and Nov 1993. Ten patients were given combination chemotherapy comprising carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen. The remaining 3 patients either rejected chemotherapy or were too ill to receive chemotherapy. Patient characteristics were as follows: there were 6 males and 4 females; age range 29-75 years; all were Chinese; sites of primary disease: extremities 8, retroorbital 1, vagina 1; sites of metastases: lymph nodes 6, skin 2, pulmonary 3, liver 1. All received the same combination chemotherapy comprising iv BCNU 150 mg/m2 q8wk, iv DTIC 220 mg/m2 x 3 days q4 wk, iv cisplatin 25 mg/m2 x 3 days q4 wk and tab tamoxifen 40 mg daily. There were 6 partial responses and no complete responses, giving a response rate of 60% with a median survival of 11.5 months. Three patients with sites of disease in the vagina, retroorbital region and metastatic liver disease had progressive disease despite chemotherapy and one died of treatment related sepsis. The 6 responders include those with metastases to the skin, nodes and/or lung. Treatment was generally tolerable. Two patients experienced delays of their subsequent cycles of treatment by 1-2 weeks due either to neutropenia and/or thrombocytopenia. This regimen is a fairly active combination against metastatic melanoma, particularly those with metastases to the nodes, skin and the lung. Those with involvement of other sites tend to respond poorly.
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PMID:Combination chemotherapy (dacarbazine, carmustine, cisplastin, and tamoxifen) in advanced melanoma. 894 55

The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has been shown previously to be enhanced markedly by the co-administration of pyrimidine deoxyribonucleosides (Lin and Prusoff, Cancer Res 47: 394-397, 1987). In the present study, we examined the cellular mechanisms underlying the augmentation effect of thymidine, one of the pyrimidine deoxyribonucleosides. It was found that thymidine did not increase the cytotoxicity of BCNU for B16/F10 melanoma cells in vitro. Instead, thymidine appeared to produce modulatory actions on the immune system of the tumor-bearing mice. More than 40% of the BCNU/ thymidine-cured mice specifically rejected secondary rechallenge with the B16/F10 tumor. Furthermore, these cured mice developed extensive depigmentation of their natural black hair, suggesting immune reactions to normal melanocytes. When spleen cells from normal mice were treated with BCNU alone, their response to T-cell mitogen phytohemagglutinin was suppressed markedly. This suppression was ablated by co-administration of BCNU with thymidine. Such BCNU/thymidine treatment also augmented the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice. Taken together, these results suggest that the enhanced antitumor activity of combined BCNU and thymidine may result from the action of thymidine on the immune effector mechanisms, which facilitate the development of antitumor immune responses in the presence of immunosuppression induced by BCNU.
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PMID:Immunomodulation and enhancement of antitumor activity by co-administration of 1,3-bis(2-chloroethyl)-1-nitrosourea and thymidine. 911 90

A phase II trial was conducted to determine the efficacy and toxicity of the addition of interferon-alpha 2b (IFN-alpha) to the chemotherapy combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin and tamoxifen (DBCT), in patients with stage III or IV melanoma. Treatment consisted of DTIC 220 mg/m2 and cisplatin 25 mg/m2 intravenously on days 1-3, BCNU 100 mg/m2 IV on day 1 only, tamoxifen 20 mg orally twice daily and IFN-alpha 5 x 10(6) units/m2 subcutaneously on days 1-5. Cycles were repeated every 4 weeks. All patients received a loading dose of tamoxifen 100 mg orally twice daily for 5 days before the first course of therapy. Of the 24 patients treated, three (13%) achieved a complete response (CR) and six (25%) a partial response (PR), for an overall response rate of 38% (95% confidence interval, 17-58%). Two patients, one who achieved a clinical CR and one a PR, had pathologically confirmed complete responses. Severe myelosuppression occurred in 47% of cycles and constitutional symptoms were common. Overall, the addition of IFN-alpha to the DBCT regimen did not appear to enhance the response rate and may have increased toxicity.
Melanoma Res 1997 Apr
PMID:A phase II study of interferon-alpha 2b with dacarbazine, carmustine, cisplatin and tamoxifen in metastatic melanoma. 916 81

L-buthionine-S,R-sulfoximine (BSO) selectivley inhibits glutathione (GSH) synthesis. Malignant melanoma may be uniquely dependent on GSH and its linked enzymes, glutathione S-transferase (GST) and GSH-peroxidase, for metabolism of reactive orthoquinones and peroxides produced during melanin synthesis. We compared the in vitro effects of BSO on melanoma cell lines and fresh melanoma specimens (n = 118) with breast and ovarian cell lines and solid tumors (n = 244). IC50 values (microM) for BSO on melanoma, breast and ovarian tumor specimens were 1.9, 8.6, and 29, respectively. The IC90 for melanoma was 25.5 microM, a level 20-fold lower than steady state levels achieved clinically. The sensitivity of individual specimens of melanoma correlated with their melanin content (r = 0.63). BSO synergistically enhanced BCNU activity against melanoma cell lines and human tumors. We followed GSH levels, GST enzyme activity, GST isoenzyme profiles and mRNA levels after BSO. BSO (50 microM) treatment for 48 hr resulted in a 95% decrease in ZAZ and M14 melanoma cell line GSH levels, and a 60% decrease in GST enzyme activity. GST-mu protein and mRNA levels were significantly reduced in both cell lines. GST-pi expression was unaffected. These data suggest that BSO action on melanoma may be related to GSH depletion, diminishing the capacity to scavenge toxic metabolites produced during melanin synthesis. We report here for the first time that BSO enhancement of alkylator action may be related in part to down regulation of GST. BSO may be a clinically useful adjunct in the treatment of malignant melanoma.
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PMID:Selective and synergistic activity of L-S,R-buthionine sulfoximine on malignant melanoma is accompanied by decreased expression of glutathione-S-transferase. 926 31


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