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 radiosensitivity. Resistance can be reverted selectively by stimulation of the cGMP-dependent transduction pathway with sodiumnitroprussid (SNP, 1). In the present study combined thermo-chemotherapy is demonstrated to overcome cisplatin resistance at mild hyperthermic temperature. Between 37 degrees C and 43 degrees C, heat alone has almost the same cytotoxic effect on SSK-R3 cells and the parental SSK cells. If cisplatin exposure is carried out at 40 degrees C for 1 hour, there is an increase in drug sensitization for both cell lines, but the thermal enhancement 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 sensitivity in the SSK-R3 cells. Upon further rise of the exposure temperature to 43 degrees C, the cytotoxic effect of heat alone dominates in both cell lines. The radiosensitivity can be increased to the same extent 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 demonstrate a dominant role of mild, clinically relevant hyperthermic temperature to enhance cisplatin sensitivity and selectively revert cisplatin resistance in SSK-R3 cells. Possible mechanisms underlying this radiation-induced cisplatin resistance are discussed.