Metabolism and radiosensitization of 4,5-dimethylmisonidazole, a ring-substituted analog of misonidazole.

4,5-Dimethylmisonidazole (DMM) is a ring-substituted derivative of the 2-nitroimidazole, misonidazole. 2-Nitroimidazoles are able to sensitize radioresistant hypoxic cells, and to kill them outright through bioreductive metabolism. The toxic process is believed to reflect the consequences of reductively activated drugs forming adducts with cellular (macro)molecules. Both this process and the radiosensitizing activity are thought to correlate with the electron affinity of radiosensitizing agents. In the present study, methyl groups were added to the imidazole ring of misonidazole in order to hinder adduct formation with cellular molecules after reductive-activation of the compound. It was anticipated that this would substantially decrease the hypoxic-cell toxicity of the parent drug. The presence of the two methyl groups reduced the half-wave reduction potential of DMM by about 70 mV, so we expected that its radiosensitizing ability would also decrease. In direct comparison with misonidazole, DMM, at equimolar concentrations, showed dramatically reduced binding to cellular macromolecules under bioreductive conditions, both in vivo, using a liver perfusion system, and in vitro, using tissue culture cells incubated under extreme hypoxia. However, DMM was only moderately less toxic than the parent compound, and showed greatly diminished radiation sensitization capacity. Since the decrease in toxicity was much less than expected, and the decrease in radiosensitization was much more than expected, this compound may be an important drug for continuing studies on the mechanisms of radiation sensitization, binding and cytotoxicity caused by electron affinic drugs.