DNA cleavage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (SR4233): Evidence for involvement of hydroxyl radical

被引:128
作者
Daniels, JS
Gates, KS
机构
[1] UNIV MISSOURI,DEPT CHEM,COLUMBIA,MO 65211
[2] UNIV MISSOURI,DEPT BIOCHEM,COLUMBIA,MO 65211
关键词
D O I
10.1021/ja9510774
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
3-Amino-1,2,4-benzotriazine 1,4-dioxide (SR4233, WIN59075, tirapazamine, 1) is a clinically promising antitumor agent that requires bioreductive activation, selectively kills oxygen-deficient cells, and is believed to derive its biological activity from DNA cleavage. Using a xanthine-xanthine oxidase enzyme system as a one-electron reductant to activate 1 for DNA cleavage, it has been found that radical scavengers such as mannitol, dimethyl sulfoxide, ethanol, methanol, and tert-butyl alcohol significantly inhibit drug-dependent DNA cleavage. Compound 1, in concert with the xanthine-xanthine oxidase system, converts DMSO to methanesulfinic acid, a reaction characteristic of hydroxyl radical. In addition, treatment of a P-32-labeled restriction fragment with reductively activated 1 results in cleavage at every base pair, with little sequence specificity, consistent with involvement of a highly reactive, nonselective agent such as hydroxyl radical. These results strongly support the involvement of radicals in the cleavage of DNA by 1 and are consistent with hydroxyl radical as the major DNA-cleaving species generated by reduction of 1.
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收藏
页码:3380 / 3385
页数:6
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