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

Cancer Drug Resistance 2019年第4期2卷 994-1001页

作者： William H.Gmeiner Department of Cancer Biology Wake Forest School of MedicineWinston-SalemNC 27157USA

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.

关键词： dna topoisomerase 1 cancer chemotherapy cytarabine gemcitabine fluoropyrimidine

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