FLUDARABINE AS A MODULATOR OF CISPLATIN ACTIVITY IN HUMAN TUMOR PRIMARY CULTURES AND ESTABLISHED CELL-LINES

The potential of the purine analogue fludarabine (9-beta-D-arabinofura nosyl-2-fluoroadenine-5' monophosphate) as a modulator of cisplatin cy totoxicity was investigated in four established cell lines and 20 prim ary cultures of human melanoma and ovarian cancer. Tumour cells were e xposed to fludarabine and cisplatin, alone or in combination, for 4 h. Fludarabine did not affect the growth of ovarian cancer cell lines, w hereas it induced a marked and dose-dependent inhibition of proliferat ion in melanoma cell lines. In primary cultures of both histotypes, th e 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 co mbination was seen in 5 of 10 melanoma and 4 of 10 ovarian cancer prim ary 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 t he remaining cultures, the interaction between fludarabine and cisplat in was additive. The alkaline filter elution analysis performed on pri mary cultures showed that the synergistic interaction between the two drugs was paralleled by an increase in the extent and persistence of t he cisplatin-induced DNA interstrand crosslinks. Our results indicate that fludarabine can enhance cisplatin cytotoxic activity in human tum our primary cultures from ovarian cancer and malignant melanoma. Such an effect may be partially due to an interference by fludarabine on ci splatin-induced DNA adduct metabolism and repair. Copyright (C) 1996 E lsevier Science Ltd