We have extended our previous studies regarding the cellular aspects of DNA damage and repair, as they relate to platinum-based anti-cancer chemotherapeutic agents. Recent studies indicate that human ovarian cancer cells made resistant to Cis-platin exhibits moderate cross-resistance to ormaplatin (tetraplatin). This cross-resistance is not explained by differences in drug accumulation or DNA repair, but is associated with reduced platinum-DNA adduct formation (and possibly cytosolic inactivation of drug). We have also investigated the role(s) of two other agents, taxol and interleukin-la, in the modulation of platinum-DNA damage and repair. Current data show that a sequence-dependent synergistic cytotoxicity of taxol with cisplatin in cisplatin-resistant human ovarian cancer cells, is associated with reduced repair of cisplatin-DNA damage, suggesting that this is the primary mechanism of synergism between these two agents. This effect is not mediated through reduced mRNA expression of excision repair genes. Highly synergistic cytotoxicity is also observed in human ovarian cancer cells exposed simultaneously to cisplatin and interleukin-la. This is associated with increased cisplatin accumulation, and increased formation of platinum-DNA adducts, as well as a significant inhibition of the ability of cells to repair platinum-DNA damage. Based on the ability of interleukin-la to decrease high energy phosphates in tumor cells, this may be attributed to a disruption of the activities of ATP-dependent protein complexes that mediate excision repair.
