Rabik Cara A, Njoku Maria Chidiamara, Dolan M Eileen
Department of Medicine, Committee on Cancer Biology, Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL 60637, USA.
Cancer Treat Rev. 2006 Jun;32(4):261-76. doi: 10.1016/j.ctrv.2006.03.004. Epub 2006 May 15.
DNA adducts at the O6-position of guanine are a result of the carcinogenic, mutagenic and cytotoxic actions of methylating and chloroethylating agents. The presence of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) renders cells resistant to the biological effects induced by agents that attack at this position. O6-Benzylguanine (O6-BG) is a low molecular weight substrate of AGT and therefore, results in sensitizing cells and tumors to alkylating agent-induced cytotoxicity and antitumor activity. Presently, chemotherapy regimens of O6-BG in combination with BCNU, temozolomide and Gliadel are in clinical development. Other ongoing clinical trials include expression of mutant AGT proteins that confer resistance to O6-BG in bone marrow stem cells, in an effort to reduce the potential enhanced toxicity and mutagenicity of alkylating agents in the bone marrow. O6-BG has also been found to enhance the cytotoxicity of agents that do not form adducts at the O6-position of DNA, including platinating agents. O6-BG's mechanism of action with these agents is not fully understood; however, it is independent of AGT activity or AGT inactivation. A better understanding of the effects of this agent will contribute to its clinical usefulness and the design of better analogs to further improve cancer chemotherapy.
鸟嘌呤O6位的DNA加合物是甲基化和氯乙基化剂致癌、致突变和细胞毒性作用的结果。DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）的存在使细胞对在该位置起作用的试剂诱导的生物学效应具有抗性。O6-苄基鸟嘌呤（O6-BG）是AGT的低分子量底物，因此可使细胞和肿瘤对烷基化剂诱导的细胞毒性和抗肿瘤活性敏感。目前，O6-BG与卡莫司汀、替莫唑胺和格利雅得联合的化疗方案正在临床开发中。其他正在进行的临床试验包括在骨髓干细胞中表达赋予对O6-BG抗性的突变AGT蛋白，以降低烷基化剂在骨髓中潜在的增强毒性和致突变性。还发现O6-BG可增强不在DNA的O6位形成加合物的试剂的细胞毒性，包括铂类试剂。O6-BG与这些试剂的作用机制尚未完全了解；然而，它独立于AGT活性或AGT失活。更好地了解该试剂的作用将有助于其临床应用，并有助于设计更好的类似物以进一步改善癌症化疗。
