title: Effect of misonidazole pretreatment on nitrogen mustard-induced DNA cross-linking in mouse tissues in vivo.
abstract: In the present study we have used the alkaline elution technique to study the effect of misonidazole (MISO) on the initial amount of DNA cross-linking in various normal and neoplastic tissues of C3H mice treated with nitrogen mustard (HN2) in vivo. Tissue samples for analysis of the cross-links were prepared 1 h after injection with HN2 to minimize the effect of subsequent repair processes on the yield of lesions. For mice receiving HN2 alone, the greatest level of cross-linking was found in spleen and jejunum, with the liver showing the lowest level. In animals that had been pretreated with MISO (1 mg g-1, i.p.) for 0.5 h prior to injection with HN2, the amount of cross-linking in the spleen and jejunum was not affected by MISO; however, in all other tissues that were examined, cross-linking was enhanced by MISO to a varying extent depending on the specific tissue. The greatest enhancement was observed in the liver (X 6) and kidney (X 3.1), both of these tissues showing a greater enhancement than either of the two fibrosarcomas. The potentiation of HN2 cross-linking in a particular tissue correlated well with two cellular processes that are known to be nitroreduction-dependent in vitro, namely, the degree of MISO-induced GSH depletion and the binding of MISO to cellular macromolecules. Thus, the potentiation of cross-linking in normal tissues such as liver and kidney, and by inference in tumours, may be intimately related to the generation and/or accumulation of nitro-reduced MISO metabolites in those tissues.
mesh_terms: D000818:Animals; D003432:Cross-Linking Reagents; D004247:DNA / Q000378:metabolism*; D004357:Drug Synergism; D005354:Fibrosarcoma / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008466:Mechlorethamine / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D009593:Nitroimidazoles; D008466:Mechlorethamine; D008920:Misonidazole; D004247:DNA