Postirradiation Modification of Tumor Blood Flow: A Method to Increase the Effectiveness of Chemical Radiosensitizers

The effect of postirradiation hypoxia induced by administration of the vasodilator hydralazine on the efficacy of misonidazole and RSU-1069 used in combination with radiation has been evaluated. Studies with the Lewis lung carcinoma indicate that hydralazine at a dose of 5 mg/kg reduces tumor blood flow and consequently increases the amount of hypoxia in the tumor tissue. Administration of hydralazine immediately after radiation treatment increased the amount of cell kill. However, the increase in cell kill was more pronounced when hydralazine was used in treatment regimes in which misonidazole (0.2 mg/g) or RSU-1069 (0.02 mg/g) was administered pre- or postirradiation. The finding that similar effects are observed if the nitroimidazoles were administered either before or after radiation in the regimes involving hydralazine suggests that the enhanced cell killing observed is due to hypoxic cell cytotoxicity. In contrast to the effects of hydralazine on the response of tumors to radiation plus misonidazole or RSU-1069, it has no effect on the response of mouse intestine to such treatment regimes. Thus therapeutic gain may accrue from the use of hydralazine in radiation treatments which incorporate the nitroimidazole radiosensitizers misonidazole and RSU-1069.