Direct evidence for bimodal DNA damage induced by tirapazamine
Direct evidence for bimodal DNA damage induced by tirapazamine
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DOI：
10.1021/tx980184j
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发表时间：
1998-11-01
影响因子：
4.1
通讯作者：
Greenberg, MM
中科院分区：
文献类型：
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作者：
Daniels, JS;Gates, KS;Greenberg, MM
通过研究抗肿瘤药物与在生物聚合物内的特定位点独立产生的寡核苷酸自由基之间的反应，证明了替拉扎明（1, 3-氨基-1,2,4-苯并三嗪 1,4-二氧化物，SR4233）修复 DNA 自由基损伤的能力。使用β-巯基乙醇作为竞争剂，确定替拉扎明以类似于 2 x 10(8) M-1 s(-1) 的速率常数捕获 C1'-核苷酸自由基。产物和同位素标记研究表明，替拉扎明通过共价加合物形成与自由基反应，这主要是由 N-氧化物氧的反应产生的。无法观察到中间共价加合物，但推测其分解成碱性不稳定的2'-脱氧核糖内酯损伤。这些实验证实了最近提出的建议，即替拉扎明可以作为 O-2 的替代品，将 DNA 自由基转化为有毒链损伤事件。
The ability of tirapazamine (1, 3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233) to fix DNA radical lesions is demonstrated by studying the reaction between the antitumor drug and an oligonucleotide radical that is independently produced at a defined site within a biopolymer. Using beta-mercaptoethanol as a competitor, it was determined that tirapazamine traps a C1'-nucleotide radical with a rate constant of similar to 2 x 10(8) M-1 s(-1) Product and isotopic labeling studies suggest that tirapazamine reacts with the radical via covalent adduct formation, resulting primarily from reaction at the N-oxide oxygen. Intermediate covalent adducts could not be observed, but are postulated to decompose to the alkaline labile 2'-deoxyribonolactone lesion. These experiments affirm recent proposals suggesting that tirapazamine can serve as a surrogate for O-2 in converting DNA radicals into toxic strand damage events.