Radiosensitization by Misonidazole (Ro 07-0582) The Importance of Timing and Tumor Concentration of Sensitizer

Abstract

The radiosensitizing effect of misonidazole (Ro 07-0582) is presented for 4 mouse tumors. The interval between administration of the drug and irradiation had a large effect on the extent to which hypoxic tumor cells are sensitized. The optimal time for irradiation differed in the different tumors and ranged from 15-120 min. This delayed effectiveness probably relates to the time required for diffusion of the drug to the critical hypoxic regions and its concentration in those regions to reach a maximum. Drug concentrations were measured in whole blood and tumors using GLC. The tumor concentrations ranged from 20-70% of the blood level in the 4 tumors; in man it was 40-107%. The in vivo radiosensitizing effect of the drug at these measured concentrations in tumors is similar to that achieved in vitro. The apparent loss in radiosensitizer effectiveness in mouse tumors in vivo relative to in vitro results is due to lower concentration in tumors than in serum, because of the short metabolic half-life in mice.