Hyperthermia, adriamycin transport, and cytotoxicity in drug-sensitive and -resistant Chinese hamster ovary cells.

Adriamycin cytotoxicity and membrane permeability to Adriamycin were studied at elevated temperatures in a drug-sensitive Chinese hamster ovary cell line and in a pleiotropic drug-resistant mutant to determine whether hyperthermia can overcome this form of acquired drug resistance. In drug-sensitive cells Adriamycin cytotoxicity, measured by colony survival studies, increased at temperatures as low as 38 degrees C, and at 43 degrees C, the combined effect of Adriamycin and hyperthermia exceeded the predicted additive effect by a factor of 10. There was a marked increase in the rate of [14C]Adriamycin uptake between 37 degrees C and 45 degrees C. Although the rate of Adriamycin efflux was also increased, intracellular drug levels at equilibrium were higher at elevated temperatures. The magnitude of the increase in intracellular drug levels at elevated temperatures was insufficient to account for the larger increase in cytotoxicity observed. We were unable to increase membrane permeability to Adriamycin or to increase Adriamycin cytotoxicity in the drug-resistant Chinese hamster ovary cell line by the use of hyperthermia; however, the drug-resistant cells were not cross-resistant to hyperthermia. Therefore, heat may be effective against residual tumor cells which are resistant to chemotherapy.