P-glycoprotein is overexpressed and functional in severely heat-shocked hepatoma cells.

BACKGROUND

Hyperthermia is used in the treatment of some human malignancies. Thermotolerance may interfere with the efficacy of hyperthermic treatment, and thermotolerant cells may also display an enhanced resistance to some anticancer drugs. We have earlier isolated stable heat-resistant rat hepatoma variants and examined whether heat resistance influenced the drug sensitivity of the cells.

MATERIALS AND METHODS

Heat-resistant variants were isolated by ten repeated cycles of heat exposure at 45 degrees C for 80 min. Highly multidrug-resistant variants were isolated by stepwise selection with colchicine.

RESULTS

The heat-resistant variants became moderately multidrug resistant. This resistance was further increased by stepwise selection with colchicine (highly multidrug resistant variants). The levels of P-glycoprotein were elevated both in moderately and highly drug resistant variants. Decreased retention of antitumor drugs was observed in the multidrug resistant variants, verapamil increased doxorubicin retention significantly. Estradiol was almost without effect, while tamoxifen increased the drug uptake. Amplification of the MDR gene occurred in a part of the highly multidrug resistant variants.

CONCLUSIONS

Acquired stable heat resistance of cancer cells can prevent the efficacy not only of hyperthermic treatment, but also the success of chemotherapy.