PMID: 8603406Apr 1, 1996Paper

Dual action of tirapazamine in the induction of DNA strand breaks

Cancer Research
G D Jones, M Weinfeld

Abstract

Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide, SR 4233) is the lead compound of a new class of hypoxic cell cytotoxins showing considerable antitumor activity. Hypoxic cytotoxicity of tirapazamine is believed to be mediated by free radical attack of its one-electron reduced metabolite on DNA, but little is known about the DNA lesions induced by the drug. Using the anoxic xanthine/xanthine oxidase system to effect one-electron reduction of tirapazamine under controlled conditions, we studied the action of the drug toward pUC18 and calf thymus DNA. Agarose gel electrophoresis indicated that tirapazamine causes substantially higher levels of single-strand breakage than double-stand breakage. The 5' DNA termini at the single-strand breaks were shown to be phosphorylated. Little, if any, base damage was observed when the damaged DNA was analyzed by a 32P-postlabeling assay. The major detectable lesion (comprising approximately 32% of the 3' ends of tirapazamine-induced single-strand breaks) was the phosphoglycolate moiety, which is caused by deoxyribose fragmentation. Since phosphoglycolate formation requires the addition of oxygen, we conclude that tirapazamine acts in a dual fashion to produce phosphoglycolates: (a) to gen...Continue Reading

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