Misonidazole is a nitroimidazole which is undergoing clinical trials as a hypoxic cell radiosensitizer. In addition to being a radiosensitizer misonidazole depletes NPSH, produces cytotoxicity, covalently binds to cell macromolecules, covalently binds to glutathione and produces chemosensitization. Preincubation of misonidazole with hypoxic cells increases the radiosensitization effect of misonidazole. The cytotoxicity, increased radiation effect and chemosensitization all may be related changes in the cellular levels of NPSH. The discovery of chemosensitization and hypoxic cell cytotoxicity has lead some workers to propose the utilization of nitroimidazoles as adjuncts in chemotherapy. This approach has been limited by the lack of knowledge of the mechanism(s) by which these effects are produced and the relative potency of the available compounds. The mechanisms by which these diverse effects are produced have not been determined although the covalent binding of misonidazole to glutathione and cell macromolecules is an appealing mechanism to account for the observed biological actions. An alternative explanation of the activities of misonidazole is the interaction of a radical ion metabolite with cell components. The importance of covalent binding in misonidazole's mechanism of action will be determined by the synthesis of misonidazole analogs in which the position of covalent binding on the imidazole ring (in vivo) is blocked. We will determine the ability of the target compounds to: radiosensitize hypoxic cells including preincubation studies, deplete NPSH, covalently bind to GSH, covalently bind to cell macromolecules, deplete protein thiols, and be cytotoxic. The objective of the proposal is to determine the relative importance of covalent binding in the mechanism(s) by which misonidazole produces its biological effects. An understanding of the mechanism by which misonidazole results in NPSH depletion, cytoxicity, and chemosensitization will provide leads for the synthesis of new compounds which are specifically designed to exploit what appears to be a novel mechanism of antineoplastic activity for hypoxic tissue.
| Born, J L; Smith, B R; Harper, N et al. (1992) Metabolism and radiosensitization of 4,5-dimethylmisonidazole, a ring-substituted analog of misonidazole. Biochem Pharmacol 43:1337-44 |
| Chacon, E; Morrow, C J; Leon, A A et al. (1988) Regioselective formation of a misonidazole-glutathione conjugate as a function of pH during chemical reduction. Biochem Pharmacol 37:361-3 |
