Pharmacology and toxicology of sensitizers: mechanism studies.

Nitroimidazoles are being studied extensively as hypoxic cell radiosensitizers. Besides their ability to selectively sensitize hypoxic cells to radiation, which depends on the parent compound, nitroimidazoles have a variety of other effects in vitro, in vivo and clinically which appear to require reductive metabolism. These other effects include direct cytotoxicity to hypoxic cells, mutagenicity and antimicrobial effects. As a first step to suggesting possible mechanisms for these other biological effects, a summary has been made of the known oxidative and reductive products of the two most widely studied radiosensitizers, metronidazole and misonidazole. Focussing on reductive products, it is clear that a great variety exists which are or may be reactive with biological molecules. Knowledge about the reduction chemistry of nitroimidazoles is new and far from complete. As a second step to suggesting possible mechanisms for these biological effects, it is important to view the problem in terms of the in vivo situation where distribution and sites of metabolism of the drug and its reduction products will be important factors. Variables such as levels of tissue oxygenation and nitroreductase activity will be important to assess. Combining basic information about the reduction chemistry of nitroimidazoles with knowledge about the pharmacology of drugs and their reduced products should allow a better assessment of mechanism of action as well as a better implementation of these drugs clinically.