Repair of 3-methyladenine and abasic sites by base excision repair mediates glioblastoma resistance to temozolomide.
Repair of 3-methyladenine and abasic sites by base excision repair mediates glioblastoma resistance to temozolomide.
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DOI：
10.3389/fonc.2012.00176
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发表时间：
2012
影响因子：
4.7
通讯作者：
Silber JR
中科院分区：
文献类型：
--
作者：
Bobola MS;Kolstoe DD;Blank A;Chamberlain MC;Silber JR
烷化剂长期以来在胶质母细胞瘤（GBM）的辅助治疗中发挥着核心作用。最近，纳入替莫唑胺（TMZ），口服给药的甲基化剂，具有低全身毒性，在放疗期间和之后显着提高生存率。大量的体外和体内证据表明，TMZ诱导的O6-甲基鸟嘌呤（O6-meG）介导GBM细胞杀伤。此外，O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）（从DNA中去除O6-meG的唯一人类修复蛋白）的低表达或不表达通常与TMZ治疗的GBM的较长生存期相关，从而促进了开发MGMT抑制剂以对抗耐药性的兴趣。然而，TMZ的临床疗效不太可能仅仅是由于O6-meG，因为该试剂产生大约十几个额外的DNA加合物，包括细胞毒性N3-甲基腺嘌呤（3-meA）和脱碱基位点。3-meA和脱碱基位点的修复，这两者都产生了更大的丰度比O6-meG，介导的碱基切除修复（BER）途径，并发生独立的O6-meG的去除。这些观察结果表明BER活性也是增强TMZ细胞毒性的策略的潜在靶标。在这里，我们审查的证据表明，3-meA和无碱基位点介导杀死GBM细胞。我们还提出了在体外和体内的证据表明，烷基腺嘌呤-DNA糖基化酶，唯一的修复活动，切除3-meA的DNA，和Ape1，主要的人类脱碱基位点核酸内切酶，介导TMZ耐药GBM和代表潜在的抗耐药靶标。
Alkylating agents have long played a central role in the adjuvant therapy of glioblastoma (GBM). More recently, inclusion of temozolomide (TMZ), an orally administered methylating agent with low systemic toxicity, during and after radiotherapy has markedly improved survival. Extensive in vitro and in vivo evidence has shown that TMZ-induced O6-methylguanine (O6-meG) mediates GBM cell killing. Moreover, low or absent expression of O6-methylguanine-DNA methyltransferase (MGMT), the sole human repair protein that removes O6-meG from DNA, is frequently associated with longer survival in GBMs treated with TMZ, promoting interest in developing inhibitors of MGMT to counter resistance. However, the clinical efficacy of TMZ is unlikely to be due solely to O6-meG, as the agent produces approximately a dozen additional DNA adducts, including cytotoxic N3-methyladenine (3-meA) and abasic sites. Repair of 3-meA and abasic sites, both of which are produced in greater abundance than O6-meG, is mediated by the base excision repair (BER) pathway, and occurs independently of removal of O6-meG. These observations indicate that BER activities are also potential targets for strategies to potentiate TMZ cytotoxicity. Here we review the evidence that 3-meA and abasic sites mediate killing of GBM cells. We also present in vitro and in vivo evidence that alkyladenine-DNA glycosylase, the sole repair activity that excises 3-meA from DNA, and Ape1, the major human abasic site endonuclease, mediate TMZ resistance in GBMs and represent potential anti-resistance targets.