Fludarabine as a modulator of cisplatin activity in human in tumour primary cultures and established cell lines

The potential of the purine analogue fludarabine (9-β-D-arabinofuranosyl-2-fluoroadenine-'5 monophosphate) as a modulator of cisplatin cytotoxicity was investigated in four established cell Lines and 20 primary cultures of human melanoma and ovarian cancer. Tumour cells were exposed to fludarabine and cisplatin, alone or in combination, for 4 h. Fludarabine did not affect the growth of ovarian cancer cell lines, whereas it induced a marked and dose-dependent inhibition of proliferation in melanoma cell lines. In primary cultures of both histotypes, the purine analogue did not-induce appreciable antiproliferative effects. Combined cisplatin-fludarabine treatment caused additive effects in all established cell lines. Conversely, a synergistic effect-of the combination was seen in 5 of 10 melanoma and 4 of 10 ovarian cancer primary cultures, with a dose-modifying factor ranging from 2.1 to 3.9 for melanomas and from 4.0 to 7.5 for ovarian cancers, respectively. In the remaining cultures, the interaction between fludarabine and cisplatin was additive. The alkaline filter elution analysis performed on primary cultures showed that the synergistic interaction between the two drugs was paralleled by an increase in the extent and persistence of the cisplatin-induced DNA interstrand cross-links. Our results indicate that fludarabine can enhance cisplatin cytotoxic activity in human tumour primary cultures from ovarian cancer and malignant melanoma. Such an effect may be partially due to an interference by fludarabine on cisplatin-induced DNA adduct metabolism and repair.