Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase
Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase
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DOI：
10.1016/j.bcp.2007.09.022
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发表时间：
2008-02-01
影响因子：
5.8
通讯作者：
Pegg, Anthony E.
中科院分区：
文献类型：
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作者：
Fang, Qingming;Loktionova, Natalia A.;Pegg, Anthony E.
人DNA修复蛋白O-6-烷基鸟嘌呤-DNA烷基转移酶（hAGT）是对一些治疗性烷化剂的抗性的重要来源，并且通过使用hAGT抑制剂来规避这种抗性的尝试已经进入临床试验。已经描述了编码hAGT的MGMT基因中的几种人类多态性，包括L 84 F和连锁的双重改变I143 V/K178 R。我们已经研究了这些变体和更罕见的变体W 65 C通过O-6-苄基鸟嘌呤的失活，其目前处于临床试验中，以及许多其它含有叶酸衍生物（O-4-苄基叶酸、O-6-苄基-2 '-脱氧鸟苷的3'和5'叶酸酯和O-6-（对羟甲基）苄基鸟嘌呤的叶酸γ酯）的第二代hAGT抑制剂。I143 V/K178 R变异体对所有这些化合物都有抗性。电阻仅由I143 V变化引起。这些结果表明，应考虑hAGT抑制剂临床试验中患者中I143 V/K178 R变异的频率及其与反应的相关性。(c)2007年爱思唯尔公司All rights reserved.
The human DNA repair protein O-6-alkylguanine-DNA alkyltransferase (hAGT) is an important source of resistance to some therapeutic alkylating agents and attempts to circumvent this resistance by the use of hAGT inhibitors have reached clinical trials. Several human polymorphisms in the MGMT gene that encodes hAGT have been described including L84F and the linked double alteration I143V/K178R. We have investigated the inactivation of these variants and the much rarer variant W65C by O-6-benzylguanine, which is currently in clinical trials, and a number of other second generation hAGT inhibitors that contain folate derivatives (O-4-benzylfolic acid, the 3' and 5' folate esters of O-6-benzyl-2'-deoxyguanosine and the folic acid gamma ester of O-6-(p-hydroxymethyl)benzylguanine). The I143V/K178R variant was resistant to all of these compounds. The resistance was due solely to the I143V change. These results suggest that the frequency of the I143V/K178R variant among patients in the clinical trials with hAGT inhibitors and the correlation with response should be considered. (c) 2007 Elsevier Inc. All rights reserved.