RESTORATION OF CISPLATIN SENSITIVITY BY MILD HYPERTHERMIA IN RADIATION-INDUCED CISPLATIN-RESISTANT MOUSE FIBROSARCOMA CELLS

Moderate cisplatin resistance has been induced in murine fibrosarcoma cells SSK-R3 by low-dose irradiation without associated changes in rad iosensitivity. Resistance can be reverted selectively by stimulation o f the cGMP-dependent transduction pathway with sodiumnitroprussid (SNP , 1). In the present study combined thermo-chemotherapy is demonstrate d to overcome cisplatin resistance at mild hyperthermic temperature. B etween 37 degrees C and 43 degrees C, heat alone has almost the same c ytotoxic effect on SSK-R3 cells and the parental SSK cells. If cisplat in exposure is carried out at 40 degrees C for 1 hour, there is an inc rease in drug sensitization for both cell lines, but the thermal enhan cement ratio (TER) is higher in the resistant cells. At 42 degrees C, the survival curves of the resistant SSK-R3 cells and the parental SSK cells almost coincide, resulting in thermal enhancement factors of 5. 4 and 3.2, respectively, and restoration of the original cisplatin sen sitivity in the SSK-R3 cells. Upon further rise of the exposure temper ature to 43 degrees C, the cytotoxic effect of heat alone dominates in both cell lines. The radiosensitivity can be increased to the same ex tent in both cell lines after one hour exposure to 42 degrees C. SNP, which selectively reverses cisplatin resistance at 37 degrees C, does not exhibit additional differential cisplatin sensitization on SSK-R3 cells compared to the SSK cells at 42 degrees C. These results demonst rate a dominant role of mild, clinically relevant hyperthermic tempera ture to enhance cisplatin sensitivity and selectively revert cisplatin resistance in SSK-R3 cells. Possible mechanisms underlying this radia tion-induced cisplatin resistance are discussed.