TAMOXIFEN ENHANCES THE CYTOTOXIC EFFECTS OF THE NITROSOUREA FOTEMUSTINE - RESULTS ON HUMAN-MELANOMA CELL-LINES

Fotemustine (Fote) is a new aminoacid linked chloroethyl nitrosourea w hich has been shown to be useful in disseminated malignant melanoma. T he aim of the present study was to analyze the cytotoxic effects resul ting from the combination of antiestrogens and Fote on human melanoma cell lines. The antiestrogens tested were tamoxifen (TMX 5.10(-7) M an d 5.10(-6) M) and 40H TMX (5.10(-8) M and 5.10(-7) M). As a preliminar y step, a series of nine human melanoma cell lines was screened in ord er to identify and quantify the presence of estradiol receptors (ER) i n these cell lines. This led to selecting an ER positive (+) cell line . The drugs alone or in combination were then tested against CAL 1 ER (+) and CAL 7 ER (-) melanoma cell lines. Different sequences of drug combinations were tested using clinically compatible drug concentratio ns. For CAL I cells there was a growth inhibitory effect induced by th e antiestrogens given alone. Overall, the presence of the antiestrogen s resulted in higher cytotoxic effects than when cells were exposed to Fote alone. The lowest IC50 Fote values as compared to Fote alone wer e generated by the sequences with the antiestrogens administered befor e Fote. Significantly, these associations with antiestrogens enabled t he IC50 values of Fote to be reduced up to 80%. Globally TMX and 40H T MX had similar synergistic effects. TMX and 40H TMX had a modest influ ence on Fote cytotoxic effects against CAL 7 ER (-) cells. These data may be useful for optimal planning of future clinical trials for malig nant melanoma using antiestrogens and nitrosoureas.