In vitro and in vivo radiosensitization by 2-nitroimidazoles more electron-affinic than misonidazole.

A series of 5-substituted-methyl-2-nitroimidazoles, more electron-affinic than misonidazole (MISO), has been studied as potential hypoxic cell radiosensitizers. In vitro radiosensitization studies of these compounds showed equivalent or greater radiosensitization than MISO, while LD50 studies of the compounds found them to be, in general, more toxic to Balb/c mice than MISO. Radiosensitization experiments in vivo with compounds SR-2537, SR-2515 and SR-2553 of acceptable toxicity were not able to sensitize the EMT6 tumor to x-irradiation after a single intraperitoneal injection. However, moderate sensitization was achieved when SR-2537 was administered i.v. Rapid metabolism of these more electron-affinic compounds was suggested as a possible cause of the poor sensitization. However, when multiple i.v. injections of SR-2537 were given to maintain a constant drug level in the tumor, radiosensitization by this compound did not improve, suggesting that intact drug was either not reaching or was not penetrating the hypoxic cells.