ANALYSIS OF THE CYTOTOXIC INTERACTION BETWEEN CISPLATIN AND HYPERTHERMIA IN A HUMAN OVARIAN-CARCINOMA CELL-LINE

Expression of the heat-shock protein HSP-60 is associated with poor survival in patients with ovarian carcinoma. We examined both the nature of the interaction between hyperthermia and cisplatin (DDP) using the human ovarian carcinoma cell line 2008 and the effect on this interaction of the induction of the heat-shock response. The nature of the interaction was assessed using median-effect analysis. Despite the observation that 45-degrees-C hyperthermia increased the intracellular uptake of the DDP analog [H-3]-cis-dichloro(ethylenediamine)platinum(II) (DEP) during a 1-h exposure by 155%+/-5% (P = 0.02), median-effect analysis indicated only cytotoxic additivity (combination index at the level of 50% cell kill, 0.96+/-0.25). When cells were first exposed to hyperthermia for various periods and then allowed to incubate at 37-degrees-C for 4 h to allow induction of the heat-shock genes before being treated with DDP for 1 h, there was a very small degree of antagonism between hyperthermia and DDP (combination index at 50% cell kill, 1.11+/-0.04). Our results indicate that DDP and hyperthermia interact only in an additive manner against this human ovarian carcinoma cell line and that the induction of heat-shock proteins by hyperthermia does not significantly antagonize the activity of DDP.