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Gmeiner. Cancer Drug Resist 2019;2:994-1001 Cancer
DOI: 10.20517/cdr.2019.95 Drug Resistance

Review Open Access

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

William H. Gmeiner

Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Correspondence to: Prof. William H. Gmeiner, Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem,
NC 27157, USA. E-mail: bgmeiner@wakehealth.edu
How to cite this article: Gmeiner WH. Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs.
Cancer Drug Resist 2019;2:994-1001. http://dx.doi.org/10.20517/cdr.2019.95

Received: 12 Oct 2019 First Decision: 18 Nov 2019 Revised: 22 Nov 2019 Accepted: 29 Nov 2019 Published: 19 Dec 2019

Science Editor: Frits Peters Copy Editor: Jing-Wen Zhang Production Editor: Jing Yu

Abstract

Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1 (Top1) is the
sole target of the camptothecin (CPT) class of anticancer drugs. Over 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 breaks. Among 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 analogs. We also summarize studies
demonstrating distinct differences between Top1cc induced by nucleoside analogs and CPTs, particularly with
regard to DNA repair. Collectively, 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 redundant. In 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
elucidated. We 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.

Keywords: DNA topoisomerase 1, cancer chemotherapy, cytarabine, gemcitabine, fluoropyrimidine

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
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