The effects of misonidazole during continuous low dose rate irradiation

Hypoxic cell sensitizers have been shown to enhance the radiation effects on tumors for single and multifractionated doses of radiation given in acute exposures. Low dose rate brachytherapy provides an opportunity for short-term high dose drug administration and continuous drug exposure throughout the entire brachytherapy course. To determine the effects of misonidazole during continuous low dose rate irradiation we have exposed the EMT6/SF tumor to continuous irradiation at 4.2 and 1.64 rads/minute with and without misondiazole (at doses of 1 mg/g or 0.2 mg/g), in bilaterally nephrectomized mice, and compared the results to those obtained wih acute exposures. Radiosensitization by misonidazole at a clinically achievable plasma concentration was observed during continuous low dose rate irradiation. The DMF (dose-modifying factor) varied with drug dose and dose rate. At a dose of 1 mg/g the DMF was 2.4 at 221 rads/minute and 1.6 at 4.2 rads/minute; at 0.2 mg/g it was 1.5 at 221 rads/minute and 4.2 rads/minute and 1.4 at 1.64 rads/minute. Cytotoxicity was also observed with drug exposure greater than 6 hours. Our results suggest that it would be advantageous to sue misonidazole during low dose rate brachytherapy.