EFFECTS OF COMBINED TREATMENT OF CHEMOTHERAPEUTICS AND HYPERTHERMIA ON SURVIVAL AND THE REGULATION OF HEAT-SHOCK PROTEINS IN DUNNING R3327 PROSTATE CARCINOMA-CELLS

BACKGROUND. Hyperthermia can enhance the clinical response of chemothe rapeutic agents in prostate cancer, but optimal sequencing of this com bination therapy needs to be developed. Given the role of heat shock p roteins (HSPs) in the development of resistance (thermotolerance) to s ubsequent hyperthermic stresses as well as to certain chemotherapeutic s, the study of HSP regulation is important in the establishment of ef fective schedules in multimodal treatment strategies. METHODS. In this study we evaluated the effects of the chemotherapeutic agents cisplat in, 5-fluorouracil, and adriamycin in combination with hyperthermia. ( 43 degrees C, 1 h) on clonogenic survival and inducible HSP70 regulati on in Dunning rat adenocarcinoma of the prostate. HSP70 was analyzed b y Western blot and by measuring beta-galactosidase produced by cells s tably transfected with a gene construct containing the E. coli beta-ga lactosidase gene driven by the Drosophila HSP70 promoter. RESULTS. Col ony formation assays revealed a sensitizing effect of hyperthermia whe n simultaneously combined with each chemotherapeutic agent, resulting in a potentiated cytotoxicity compared to subsequenced treatments. The rmotolerant cells showed a significantly better survival when treated with adriamycin alone, but also when each chemotherapeutic agent was c ombined with hyperthermia. This enhanced survival was correlated with inducible HSP70 accumulation. The chemotherapeutics modified the HSP70 promoter activation induced by hyperthermia, suggesting changes in th e development of cellular thermotolerance. CONCLUSIONS. Our data revea l synergistic cytotoxic effects of the synchronous application of chem otherapeutic agents and hyperthermia on this model of prostate cancer. Furthermore, they demonstrate that the induction of HSPs in thermotol erant cells, as measured by HSP70 induction, results in a modulation t he chemotherapeutic-mediated cytotoxicity. Therefore, HSP70 is a usefu l marker of cellular resistance in multimodal approaches combining hyp erthermia and chemotherapeutic agents in the treatment of locally adva nced prostate carcinoma. (C) 1998 Wiley-Liss, Inc.