S-Alkylthiolation of O6-methylguanine-DNA-methyl transferase (MGMT) to sensitize cancer cells to anticancer therapy

被引：14

作者：

Juillerat, Alexandre

Juillerat-Jeanneret, Lucienne

机构：

[1] CHU Vaudois, Univ Inst Pathol, CH-1011 Lausanne, Switzerland

[2] Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, CH-1015 Lausanne, Switzerland

来源：

EXPERT OPINION ON THERAPEUTIC TARGETS | 2007年 / 11卷 / 03期

关键词：

alkylating agent; cancer; drug resistance; drug targeting; O-6-alkylguanine DNA alkyltransferase; O-6-methylguanine DNA methyltransferase;

D O I：

10.1517/14728222.11.3.349

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

O-6-Methylguanine DNA methyltransferase/O-6-alkylguanine DNA alkyltransferase (MGMT/AGT) removes alkyl adducts from the O-6-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 O-6-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 O-6-benzylguanine targeting defined pathways of cancer cells that can be used to improve the selectivity of O-6-benzylguanine-based inhibitors for cancer cells. Therefore, MGMT inhibitor targeting represents a reliable strategy for improving cancer therapy with alkylating agents.

引用

页码：349 / 361

页数：13

共 91 条

[21] Phase II trial of the O6-alkylguanine DNA alkyltransferase inhibitor O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea in advanced melanoma [J].