O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems.
O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems.
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DOI：
10.1016/j.bbcan.2011.12.004
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发表时间：
2012-08
影响因子：
11.2
通讯作者：
Chamberlain, Marc C.
中科院分区：
文献类型：
--
作者：
Silber, John R.;Bobola, Michael S.;Blank, A.;Chamberlain, Marc C.
神经胶质瘤是最常见的成人原发性脑肿瘤，并且总是致命的。胶质母细胞瘤（GBM）是最常见的诊断，每年在美国有12，500名新患者，并且在使用当前护理标准治疗时，中位生存期约为一年。烷化剂长期以来一直是GBM和其他胶质瘤化疗的中心。DNA修复蛋白O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）是从DNA中去除细胞毒性O 6-烷基鸟嘌呤加合物的主要人体活性，可促进GBM细胞系和异种移植物对抗神经胶质瘤烷化剂（包括替莫唑胺和BCNU）的耐药性。此外，通过免疫组织化学、生物化学活性或启动子CpG甲基化状态评估的MGMT表达与GBM对基于烷化剂的治疗的反应相关，提供了MGMT促进对烷化剂的临床抗性的证据。这些观察结果表明MGMT在指导GBM和其他胶质瘤的辅助治疗中的作用。启动子甲基化状态是临床上最易处理的MGMT测量，并且有相当大的热情探索其作为标记物的效用以分配治疗给个体患者。在这里，我们提供了一个概述MGMT的生化，遗传和生物学特性，因为它们涉及到胶质瘤的治疗。我们认为目前的方法来评估MGMT的表达，并讨论其效用作为治疗反应的预测。特别强调的是启动子甲基化状态和方法和概念上的障碍，限制其使用直接治疗。最后，我们考虑了可以提高MGMT甲基化状态在规划针对个体患者的最佳疗法中的效用的方法。
Gliomas are the most frequent adult primary brain tumor, and are invariably fatal. The most common diagnosis glioblastoma (GBM) afflicts 12,500 new patents in the U.S. annually, and has a median survival of approximately one year when treated with the current standard of care. Alkylating agents have long been central in the chemotherapy of GBM and other gliomas. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), the principal human activity that removes cytotoxic O6-alkylguanine adducts from DNA, promotes resistance to anti-glioma alkylators, including temozolomide and BCNU, in GBM cell lines and xenografts. Moreover, MGMT expression assessed by immunohistochemistry, biochemical activity or promoter CpG methylation status is associated with the response of GBM to alkylator-based therapies, providing evidence that MGMT promotes clinical resistance to alkylating agents. These observations suggest a role for MGMT in directing adjuvant therapy of GBM and other gliomas. Promoter methylation status is the most clinically tractable measure of MGMT, and there is considerable enthusiasm for exploring its utility as a marker to assign therapy to individual patients. Here, we provide an overview of the biochemical, genetic and biological characteristics of MGMT as they relate to glioma therapy. We consider current methods to assess MGMT expression and discuss their utility as predictors of treatment response. Particular emphasis is given to promoter methylation status and the methodological and conceptual impediments that limit its use to direct treatment. We conclude by considering approaches that may improve the utility of MGMT methylation status in planning optimal therapies tailored to individual patients.
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DOI：
10.1016/s0027-5107(97)00314-x
发表时间：
1998-06-05
影响因子：
2.3
作者：
Douglas, MP;Rogers, SO
通讯作者：
Rogers, SO
影响因子：
6.4
作者：
Christmann, Markus;Nagel, Georg;Kaina, Bernd
通讯作者：
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影响因子：
5.3
作者：
COSTELLO, JF;FUTSCHER, BW;PIEPER, RO
通讯作者：
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影响因子：
3.6
作者：
Chen, ZP;Malapetsa, A;Panasci, LC
通讯作者：
Panasci, LC
影响因子：
11.5
作者：
Brell, M;Tortosa, A;Graus, F
通讯作者：
Graus, F