Enhancement of Misonidazole Chemopotentiation by Mild Hyperthermia (41°C) in Vitro and Selective Enhancement in Vivo

Summary

Experiments were designed to test the hypothesis that mild heat treatment would selectively increase misonidazole (MISO) chemopotentiation of CCNU toxicity in hypoxic versus aerobic cells in vitro and in tumours in vivo via an augmentation of nitroreduction. EMT-6 cells were exposed to CCNU ± 1·0 mm MISO under aerobic or hypoxic conditions for 4 h either at a constant 37°C or at 41°C for the first hour followed by 37°C for the remaining 3 h. Chemopotentiation was not observed under aerobic conditions and heat treatment did not modify CCNU toxicity. Co-incubation with MISO and CCNU under hypoxic conditions resulted in enhanced toxicity (i.e. chemopotentiation) with either incubation protocol; however, the magnitude of the enhancement was significantly larger (P < 0·025) when 41°C incubation was included. Systemic heat treatment produced a similar enhancement of chemopotentiation in KHT tumours in C3H/HeN mice treated with MISO (0·5 mg g⁻¹) and whole body hyperthermia (41°C, 1 h) prior to administration of CCNU (15 mg kg⁻¹). Heating had no effect on CCNU response but doubled the median growth delay produced by the CCNU-MISO combination. Heat treatment did not enhance myelosuppression of the combination. Both the in vitro and in vivo data indicate that mild hyperthermia can selectively enhance the magnitude of MISO chemopotentiation.