酪氨酰-DNA磷酸二酯酶:潜在的肿瘤治疗靶点

Tyrosyl-DNA phosphodiesterases: potential targets for cancer treatment

内源性和外源性因素会造成DNA拓扑异构酶介导的DNA损伤。为了保持基因的稳定,细胞需要在多种修复酶的参与下代谢或修复这些损伤的DNA。酪氨酰-DNA磷酸二酯酶1(TDP1)和酪氨酰-DNA磷酸二酯酶2(TDP2)是近年来发现的两种DNA修复酶。它们可以分别水解DNA 3'端和5'端的酪氨酰磷酸二酯键,处理由DNA拓扑异构酶介导的DNA损伤,从而导致肿瘤细胞耐药,因此是潜在的肿瘤治疗靶点。本文讨论了其作为肿瘤治疗靶点的理论依据,分析了其抑制剂与拓扑毒剂或其他DNA损伤剂联合使用治疗肿瘤的可行性。

DNA topoisomerases-mediated DNA damages are generated from exogenous and endogenous effects, which need to be metabolized or repaired to maintain genome stability involving in many of repair enzymes. Tyrosyl-DNA phosphodiesterase 1（TDP1） and tyrosyl-DNA phosphodiesterase 2（TDP2） are two DNA repair enzymes discovered recently. TDP1 and TDP2 have the ability to hydrolyze the tyrosyl-phosphodiester bond of the phenol of tyrosine with 3＇- and 5＇-DNA end, respectively, which are contained in the metabolites of the damaged DNA mediated by topoisomerase 1 and topoisomerase 2, respectively. The abnormal activation and expression of TDP1 or TDP2 is the important reason for cancer development. Therefore, TDP1 and TDP2 have been regarded as potential targets in cancer therapy. In this review, we discuss the rationales of their potential as targets and development of their inhibitors together with topoisomerase poisons or DNA damaging agents.