Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides
Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides
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DOI：
10.1039/b502586a
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发表时间：
2005-01-01
影响因子：
3.2
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Anderson, RF;Shinde, SS;Denny, WA
揭示抗癌药物替拉帕嗪（3-氨基-1,2,4-苯并三嗪1,4-二氧化）诱导缺氧选择性细胞毒性的自由基机制，是开发临床有用的抗化疗和耐辐射缺氧肿瘤细胞的生物还原药物的途径。我们之前的研究指出，在替拉帕嗪的单电子还原和它从初始还原中间体中消除水之后，形成了一个活性苯并三嗪基自由基，并表明该物种是一种细胞毒素。本文用脉冲辐射法测定了苯并三嗪基自由基E（B-）的单电子还原电位。（H+/ B）以及它们的双电子还原代谢物苯三嗪1-氧化物E（B/B -）的单电子还原电位。发现单电子还原苯并三嗪1,4-氧化物的氧化还原依赖关系、自由基亲原性和水消除反应主要由苯并三嗪1,4-氧化物的单电子还原电位E（A/A(.-)）来跟踪。对已发表的SCCVII小鼠肿瘤细胞系的好氧和低氧克隆原细胞毒性数据与本研究测量的理化参数进行多元回归分析，发现低氧细胞毒性依赖于E（B-）。， H+/ B)，从而有力地证明了苯并三嗪基自由基是缺氧条件下活性的细胞毒性物质，而有氧细胞毒性依赖于E（B/B -）。综上所述，最大化这两个控制参数之间的差比值，并结合必要的药理学方面，将导致更有效的抗癌生物还原药物。
Revealing the free radical mechanism by which the anticancer drug tirapazamine (3-amino-1,2,4- benzotriazine 1,4- dioxide) induces hypoxia-selective cytotoxicity, is seen as a way forward to develop clinically useful bioreductive drugs against chemo-and radiation-resistant hypoxic tumor cells. Our previous studies point to the formation of an active benzotriazinyl radical following the one-electron reduction of tirapazamine and its elimination of water from the initial reduction intermediate, and have suggested that this species is a cytotoxin. In this paper we have used pulse radiolysis to measure the one-electron reduction potentials of the benzotriazinyl radicals E(B-., H+/ B) of 30 analogues of tirapazamine as well as the one-electron reduction potentials of their two-electron reduced metabolites, benzotriazine 1-oxides E(B/B.-). The redox dependencies of the back-oxidation of the one-electron reduced benzotriazine 1,4- dioxides by oxygen, their radical prototropic properties and water elimination reactions were found to be tracked in the main by the one-electron reduction potentials of the benzotriazine 1,4- dioxides E(A/A(.-)). Multiple regression analysis of published aerobic and hypoxic clonogenic cytotoxicity data for the SCCVII murine tumor cell line with the physical chemistry parameters measured in this study, revealed that hypoxic cytotoxicity is dependent on E(B-., H+/ B) thus providing strong evidence that the benzotriazinyl radicals are the active cytotoxic species in hypoxia, while aerobic cytotoxicity is dependent on E(B/B.-). It is concluded that maximizing the differential ratio between these two controlling parameters, in combination with necessary pharmacological aspects, will lead to more efficacious anticancer bioreductive drugs.