Correlation of O6-Methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity
Correlation of O6-Methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity
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DOI：
10.1200/jco.2007.11.5964
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发表时间：
2008-09-01
影响因子：
45.3
通讯作者：
Gilbert, Mark R.
中科院分区：
文献类型：
--
作者：
Hegi, Monika E.;Liu, Lili;Gilbert, Mark R.
通过O-6-甲基鸟嘌呤甲基转移酶(MGMT)直接修复DNA对烷化剂的耐药性仍然是恶性胶质瘤患者成功治疗的重要障碍。MGMT在肿瘤中的相对表达可能决定了对烷化剂的反应，而通过启动子甲基化使MGMT基因的表观遗传沉默在调节MGMT在胶质瘤中的表达起着重要作用。在接受烷化剂治疗的患者中，MGMT启动子甲基化与改善无进展和总存活率相关。克服MGMT介导的化疗耐药性的策略正在积极研究中。这些治疗包括使用无毒的MGMT的假底物抑制剂，如O6-苄基鸟嘌呤，或RNA干扰介导的MGMT的基因沉默。然而，MGMT抑制剂的全身应用受到血液毒性增加的限制。另一种策略是使用剂量密集的替莫唑胺方案来耗尽肿瘤组织中的MGMT活性。这些替代方案耐受性良好；然而，目前尚不清楚它们是否比标准剂量方案更有效，或者它们是否有效地耗尽肿瘤组织中的MGMT活性。值得注意的是，并不是所有MGMT启动子甲基化的胶质母细胞瘤患者都对烷化药物有反应，即使是有反应的患者也不可避免地会复发。在这里，我们回顾了支持MGMT作为恶性胶质瘤化疗耐药的主要机制的数据，并描述了正在进行的测试耐药调节策略的研究。
Resistance to alkylating agents via direct DNA repair by O-6-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O6-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.