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

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.