BINDING TO CELLULAR MACROMOLECULES AS A POSSIBLE MECHANISM FOR THE CYTO-TOXICITY OF MISONIDAZOLE

  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (7) , 2165-2169
Abstract
Reduction of the nitro group occurred when [14C]misonidazole was treated with Zn dust in aqueous solution in the presence of ammonium chloride. When the reduction mixture was allowed to react with calf thymus DNA or bovine albumin, radioactivity was bound to DNA and protein. Under the same conditions, misonidazole did not bind to these macromolecules. Analysis of the reduction mixture indicated that the hydroxylamine, amine and hydrazo derivatives of misonidazole were the major products. In a number of tissues of C3H mice after administration of [14C]misonidazole, radioactivity was detected in the DNA, RNA and protein fractions. Similar results were also obtained with Chinese hamster ovary cells incubated with the drug in the absence of oxygen. Nitroreduction and binding of the nitroreduction products to macromolecules is a probable mechanism for the mutagenic and cytotoxic properties of misonidazole. Misonidazole [1-(2-nitro-1-imidazolyl)-3 methoxy-2-propanol] is currently undergoing clinical investigation as a potential radiation sensitizing agent in the treatment of human cancer. In addition to its radiation-sensitizing effects on hypoxic cells, misonidazole exhibits pronounced toxicity toward hypoxic cells in the absence of radiation, and this property suggests that the drug may also have potential as an adjunct to chemotherapy.