Juillerat Alexandre, Juillerat-Jeanneret Lucienne
Institute of Chemical Sciences and Engineering, Swiss Institute of Technology of Lausanne (EPFL), Lausanne, Switzerland.
Expert Opin Ther Targets. 2007 Mar;11(3):349-61. doi: 10.1517/14728222.11.3.349.
O6-methylguanine DNA methyltransferase/O6-alkylguanine DNA alkyltransferase (MGMT/AGT) removes alkyl adducts from the O6-position of guanine in DNA. Expression of MGMT in human cancers has been associated with resistance to therapies using alkylating agents. MGMT promoter methylation regulates its expression and response to alkylating agents. A combination of O6-benzylguanine-based inhibitors of MGMT with alkylating agents improved the efficacy. However, this is associated with enhanced cytotoxicity and the induction of GC to AT transition mutations presumably also in progenitor/stem cells. A few recent studies have described analogs of O6-benzylguanine targeting defined pathways of cancer cells that can be used to improve the selectivity of O6-benzylguanine-based inhibitors for cancer cells. Therefore, MGMT inhibitor targeting represents a reliable strategy for improving cancer therapy with alkylating agents.
O6-甲基鸟嘌呤DNA甲基转移酶/O6-烷基鸟嘌呤DNA烷基转移酶（MGMT/AGT）可从DNA中鸟嘌呤的O6位去除烷基加合物。MGMT在人类癌症中的表达与对使用烷化剂的治疗产生耐药性有关。MGMT启动子甲基化调节其表达以及对烷化剂的反应。基于O6-苄基鸟嘌呤的MGMT抑制剂与烷化剂联合使用可提高疗效。然而，这与细胞毒性增强以及可能在祖细胞/干细胞中诱导GC到AT的转换突变有关。最近的一些研究描述了靶向癌细胞特定途径的O6-苄基鸟嘌呤类似物，可用于提高基于O6-苄基鸟嘌呤的抑制剂对癌细胞的选择性。因此，靶向MGMT抑制剂是一种利用烷化剂改善癌症治疗的可靠策略。
