MODULATION OF MELPHALAN AND CISPLATIN CYTOTOXICITY IN HUMAN OVARIAN-CANCER CELLS RESISTANT TO ALKYLATING DRUGS

We investigated the effect of pharmacological modulators on the cytoto xic activity of melphalan and cisplatin in human ovarian cystadenocarc inoma cells sensitive (OAW42) or resistant (OAW42MER) to bifunctional alkylating agents. By filter elution experiments we observed a reduced accumulation and a faster repair of melphalan-induced DNA Interstrand cross-links in the OAW42MER resistant cells than in the OAW42 parenta l, sensitive cells. Moreover, resistant cells were characterized by an increased level of mRNA encoding enzymes involved in the nucleotide e xcision repair pathway, such as ERCC (excision repair cross complement ing) 1 and ERCC2. Among the modulators used, the topoisomerase I inhib itor topotecan was able to increase melphalan cytotoxic activity in se nsitive and resistant cell lines. Topotecan also positively modulated cisplatin activity, although to a variable extent in the two cell line s, as a function of treatment schedule. The energolytic compound lonid amine markedly enhanced the cytotoxicity of melphalan and cisplatin, w ith a potentiating effect in the OAW42MER resistant cells almost 2-fol d that of in the OAW42 sensitive cells. No significant potentiation wa s observed by using calcium channel blockers, such as verapamil and ni modipine. Conversely, an increase in melphalan cytotoxic activity was determined by flunarizine in OAW42MER resistant cells and, to a lesser extent, in OAW42 sensitive cells. However, the calcium blocker failed to modulate cisplatin activity in both cell lines.