Hegi Monika E, Liu Lili, Herman James G, Stupp Roger, Wick Wolfgang, Weller Michael, Mehta Minesh P, Gilbert Mark R
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery BH-19-110, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland.
J Clin Oncol. 2008 Sep 1;26(25):4189-99. doi: 10.1200/JCO.2007.11.5964.
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 O(6)-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.
通过O(6)-甲基鸟嘌呤甲基转移酶（MGMT）进行直接DNA修复对烷化剂产生耐药性，仍然是恶性胶质瘤患者成功治疗的重大障碍。肿瘤中MGMT的相对表达可能决定对烷化剂的反应，而启动子甲基化导致的MGMT基因表观遗传沉默在调节胶质瘤中MGMT表达方面起着重要作用。MGMT启动子甲基化与接受烷化剂治疗患者的无进展生存期和总生存期改善相关。克服MGMT介导的化疗耐药性的策略正在积极研究中。这些策略包括用MGMT的无毒假底物抑制剂（如O(6)-苄基鸟嘌呤）进行治疗，或通过RNA干扰介导的MGMT基因沉默。然而，MGMT抑制剂的全身应用受到血液学毒性增加的限制。另一种策略是使用剂量密集的替莫唑胺方案降低肿瘤组织中的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给药方案更有效，或者它们是否能有效降低肿瘤组织中的MGMT活性。值得注意的是，并非所有MGMT启动子甲基化的胶质母细胞瘤患者都对烷化剂有反应，即使有反应的患者也不可避免地会复发。在此，我们综述了支持MGMT作为恶性胶质瘤化疗耐药主要机制的数据，并描述了正在进行的测试耐药性调节策略的研究。
