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

Fotemustine (Fote) is a new amino acid-linked chloroethyl nitrosourea which has been shown to be useful in disseminated malignant melanoma. The aim of the present study was to analyse the cytotoxic effects resu lting from the combination of anti-oestrogens and Fete on human melano ma cell lines. The anti-oestrogens tested were tamoxifen (TMX, 5 x 10( -7) mol/l and 5 x 10(-6) mol/l) and 40H TMX (5 x 10(-8) mol/l and 5 x 10(-7) mol/l). As a preliminary step, a series of nine human melanoma cell lines was screened in order to identify and quantify the presence of oestradiol receptors (ER) in these cell lines. This led to the sel ection of an ER-positive (+) cell line. The drugs alone or in combinat ion were then tested against CAL 1 ER(+) and CAL 7 ER(-) melanoma cell lines. Different sequences of drug combinations were tested using cli nically compatible drug concentrations. For CAL 1 cells, there was a g rowth inhibitory effect induced by the anti-oestrogens given alone. Ov erall, the presence of the anti-oestrogens resulted in higher cytotoxi c effects than when cells were exposed to Fete alone. The lowest IC50 Fote values as compared to Fete alone were generated by the sequences in which the anti-oestrogens were administered before Fote. Significan tly, these associations with anti-oestrogens enabled the IC50 values o f Fote to be reduced by up to 80%. Globally, TMX and 40H TMX had simil ar synergistic effects. TMX and 40H TMX had a modest influence on Fote cytotoxic effects against CAL 7 ER-negative cells. These data may be useful for optimal planning of future clinical trials for malignant me lanoma using anti-oestrogens and nitrosoureas.