Hypoxia-dependent reduction of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol by Chinese hamster ovary cells and KHT tumor cells in vitro and in vivo

Abstract

Incubation of Chinese hamster ovary cells and KHT murine fibrosarcoma tumor cells in the absence of oxygen with 1-[2-14C]nitro-1-imidazolyl)-3-methoxy-2-propanol, one of the most effective radiation sensitizers of hypoxic cells, results in the preferential reduction of 1-[2-14C]nitro-1-imidazolyl)-3-methoxy-2-propanol. The radioactivity associated with the acid-insoluble precipitate from cells incubated in nitrogen is about four times higher than that of cells incubated in air. When aqueous extracts of tissues of a C3H mouse bearing the KHT tumor, after i.p. injection with 1-[2-14C]nitro-1-imidazolyl)-3-methoxy-2-propanol, are analyzed, a reduction product is found in relatively higher yields in the tumor than in normal tissues. The relative radioactivity in the pellet from the tumor homogenate is also high in comparison with those of most normal tissues. These results provide suggestive evidence for a higher degree of hypoxic in the tumor than in most normal tissues. The formation of reduction products and their subsequent binding to macromolecules may explain the preferential toxicity of nitro compounds to mammalian cells under hypoxia conditions. These results suggest that some nitro compounds may be useful for the treatment of tumors having a high fraction of hypoxic cells even in the absence of radiation.