Modulation of cisplatin resistance by 2'-deoxy-5-azacytidine in human ovarian tumor cell lines

The sequential administration of 2'-deoxy-5-azacytidine (DAC) and cisplatin frequently results in synergistic cytotoxicity against human cancer cell lines (Frost P, et al Cancer Res 50:4572-4577, 1990) including the cisplatin resistant HEY ovarian cancer cell line. In this series of in vitro experiments the effect of DAC on cisplatin resistance was evaluated in two cisplatin resistant ovarian cell lines, C13* and A2780/DDP, and by varying the concentration ratio of DAC to cisplatin against the HEY cell line. For C13* and A2780/DDP sequential exposure to DAC and cisplatin resulted in synergy and a one to three-fold decrease in the concentration of cisplatin required to achieve defined levels of cytotoxicity. Augmentation of the synergistic interaction was also observed with the HEY line suggesting that increasing the concentration of DAC relative to cisplatin could result in improved modulation of cisplatin resistance for some highly cisplatin resistant lines. Since the concentrations of DAC and cisplatin required in vitro to observe these interactions are frequently achievable in human plasma, the clinical value of DAC modulation of cisplatin resistance could be tested in appropriately designed clinical trials.