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Chemical and biological studies of the radiosensitizer misonidazole Josephy, P. David


Misonidazole (Ro 07-0582) is a nitroheterocyclic drug which sensitizes hypoxic (oxygen-deficient) cells to the lethal action of ionising radiation. Tumours contain radioresistant hypoxic cells which may limit the usefulness of radiotherapy as a modality of cancer treatment. The use of misonidazole as an adjunct to radiotherapy may improve the local control of such tumours, and clinical trials are in progress. Misonidazole is selectively toxic to hypoxic cells, even in the absence of radiation. This effect may be related to the clinical toxicity of the drug, which limits the dose of misonidazole which may be delivered safely, and, thus, limits the effectiveness of the radiosensitizer. The selective toxicity of misonidazole is believed to be related to its metabolism in hypoxic cells. Reduction of nitroaromatic compounds, such as nitrobenzene, is inhibited by oxygen; thus, reductive activation of misonidazole to a toxic species may explain the selective action of the drug against hypoxic cells. We have studied the reductive chemistry of misonidazole, and its metabolism, using a variety of chemical and in vitro biological techniques. Ascorbic acid (vitamin C) enhances the toxicity of misonidazole to hypoxic Chinese hamster ovary (CHO) cells. This marked enhancement appears to be caused by accelerated drug metabolism in the presence of ascorbate. Chemical reduction of misonidazole by zinc dust yields a mixture of azo-misonidazole and azoxy-misonidazole. These compounds were separated by preparative reversed-phase liquid chromatography, char- acterized chemically, and tested for in vitro biological activity. Azo-misonidazole is almost non-toxic, but azoxy-misonidazole is more toxic than misonidazole itself. Misonidazole was reduced by the xanthine/xanthine oxidase (XO) system, under hypoxia. This enzymatic reduction yielded a single major product, which appears to be hydroxylamino-misonidazole. The same enzyme system also reduces azo- and azoxy-misonidazole. The metabolic transformation of ¹⁴C-misonidazole was studied, using dense suspensions of CHO cells in hypoxia. Misonidazole is converted into several polar products, and binding to acid-insoluble material (presumably macromolecules) was observed. The organic-soluble metabolite fraction contains a compound with identical chromatographic properties to the xanthine/XO product, believed to be hydroxylamino-misonidazole. The significance of these results is discussed in the context of the clinical potential of misonidazole and related drugs as radiosensitizers. The possibility of exploiting hypoxic cytotoxicity as a selective chemotherapy for hypoxic tumour cells is considered.

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