Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs

作     者：William H.Gmeiner 

作者机构：Department of Cancer BiologyWake Forest School of MedicineWinston-SalemNC 27157USA 

出 版 物：《Cancer Drug Resistance》 (癌症耐药（英文）)

年 卷 期：2019年第2卷第4期

页      面：994-1001页

学科分类：081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 070303[理学-有机化学] 0703[理学-化学] 

基　　金：Research reported in this publication was supported by the National Cancer Institute’s Cancer Center Support Grant(P30CA012197)issued to the Wake Forest Baptist Comprehensive Cancer Center.Gmeiner WH is supported by NIH grant(NIH-NCI R21 CA218933) 

主　　题：DNA topoisomerase 1 cancer chemotherapy cytarabine gemcitabine fluoropyrimidine 

摘      要：Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1(Top1)is the sole target of the camptothecin(CPT)class of anticancer *** the last 20 years,multiple studies have shown Top1 activity is modulated by non-native DNA structures and this can lead to trapping of Top1 cleavage complexes(Top1cc)and conversion to DNA double strand *** the perturbations to DNA structure that generate Top1cc are nucleoside analogs that are incorporated into genomic DNA during replication including cytarabine,gemcitabine,and 5-fluoro-2’-deoxyuridine(FdU).We review the literature summarizing the role of Top1cc in mediating the DNA damaging and cytotoxic activities of nucleoside *** also summarize studies demonstrating distinct differences between Top1cc induced by nucleoside analogs and CPTs,particularly with regard to DNA ***,these studies demonstrate that,while Top1 is a common target for both Top1 poisons such as CPT and nucleoside analogs such as FdU,these agents are not *** recent years,studies have shown that Top1 poisons and nucleoside analogs together with other anti-cancer drugs such as cisplatin cause replication stress and the DNA repair pathways that modulate the cytotoxic activities of these compounds are being *** present an overview of this evolving literature,which has implications for how targeting of Top1 with nucleoside analogs can be used more effectively for cancer treatment.