CHEMOTHERAPY-INDUCED APOPTOSIS IN MELANOMA-CELLS IS P53 DEPENDENT

Metastatic melanomas are often resistant to chemotherapy. To study whe ther the p53 mutational status affects chemosensitivity, we compared t he responses to chemotherapy of four melanoma cell lines containing th e wild-type p53 and four cell lines carrying the mutant p53. Cisplatin , at 10 mu M, virtually killed all the cells in the wild-type p53 cell lines, while 57-95% of the cells in the mutant p53 cell lines survive d (P = 0.005). After treatment with 100 nM of vincristine, on average 18% of the wild-type p53 melanoma cells survived compared with 55% of the mutant p53 cells (P = 0.04). After treatment with 40 nM, 200 nM or 1 mu M of camptothecin the survival rates were, on average, 16%, 8% a nd 4% for the wild-type p53 melanoma cells, compared with 89%, 67% and 38% for the mutant p53 cells, respectively (P = 0.00004, P = 0.003 an d P = 0.04, respectively). The anticancer agents were not toxic to nor mal melanocytes at doses inducing cytotoxicity in wild-type p53 melano ma cells. The main mechanism of cytotoxicity appears to be drug-induce d apoptosis. Cisplatin, camptothecin and vincristine all induced apopt osis in wild-type p53 melanoma cells, but not in mutant p53 cells. Our results suggest that chemotherapy-induced apoptosis in melanoma cells is p53 dependent, and mutation of the p53 gene is an indicator of dru g resistance in melanoma. (C) 1998 Rapid Science Ltd.