Department of Oncology, Instituto di Ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, 20157, Milan, Italy.,
Cytotechnology. 1998 Sep;27(1-3):165-73. doi: 10.1023/A:1008060720608.
Alkylating agents are the most widely used anticancer drugs whose main target is the DNA, although how exactly the DNA lesions cause cell death is still not clear. The emergence of resistance to this class of drugs as well as to other antitumor agents is one of the major causes of failure of cancer treatment. This paper reviews some of the best characterized mechanisms of resistance to alkylating agents. Pre- and post-target mechanisms are recognized, the former able to limit the formation of lethal DNA adducts, and the latter enabling the cell to repair or tolerate the damage. The role in the pre-target mechanisms of reduced drug accumulation and the increased detoxification or activation systems (such as DT-diaphorase, metallothionein, GST/GSH system, etc...) are discussed. In the post-target mechanisms the different DNA repair pathways, tolerance to alkylation damage and the 'downstream' effects (cell cycle arrest and/or apoptosis) are examined.
烷化剂是应用最广泛的抗癌药物，其主要作用靶点是 DNA，尽管确切的 DNA 损伤如何导致细胞死亡尚不清楚。对这类药物以及其他抗肿瘤药物的耐药性的出现是癌症治疗失败的主要原因之一。本文综述了一些对烷化剂耐药性的特征性机制。目前已经认识到了靶前和靶后机制，前者能够限制致死性 DNA 加合物的形成，后者使细胞能够修复或耐受损伤。本文讨论了药物蓄积减少和解毒或激活系统（如 DT-黄递酶、金属硫蛋白、GST/GSH 系统等）增加在靶前机制中的作用。在后靶机制中，研究了不同的 DNA 修复途径、对烷化损伤的耐受性以及“下游”效应（细胞周期停滞和/或细胞凋亡）。
