Effect of hyperthermia on intracellular drug accumulation and chemosensitivity in drug-sensitive and drug-resistant P388 leukaemia cell lines

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Abstract
Enhancements of the drug-induced cytotoxicity and modifications of drug transmembrane equilibria caused by hyperthermic treatment were analysed on P388/S and P388/R murine leukaemia cell lines. The P388/R cell line was derived from the P388/S cell line by drug selection of mutant, drug-resistant clones; it expresses a pleiotropic drug resistance towards some chemotherapeutic drugs such as doxorubicin, daunorubicin and etoposide, but is only weakly resistant towards other drugs as cis-diammine-dichloroplatinum. Hyperthermic treatment enhanced the drug cytotoxic effects much more on the P388/R cell line than on the P388/S line, but the cytotoxic enhancements were consistent only for the drug towards which the P388/R cell line expresses pleiotropic resistance. Intracellular drug accumulation analysis and drug transmembrane equilibria determinations indicated that the resistance of both cell lines to the intracellular drug was not affected by hyperthermic treatment, whereas variations in drug influx, but not in drug extrusion, were induced by heat treatment. The study suggested, therefore, that hyperthermia does not modify intracellular chemosensitivity of either cell line, but acts on membrane permeability by facilitating attainment of the intracellular drug concentrations needed to cause the cytotoxic effect.