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

Area of Science:

• Molecular Biology
• Cancer Research
• Pharmacology

Background:

• DNA topoisomerase 1 (Top1) is a validated cancer chemotherapy target.
• Top1 activity is modulated by DNA structural changes, leading to Top1 cleavage complexes (Top1cc) and DNA double-strand breaks.
• Nucleoside analogs (e.g., cytarabine, gemcitabine, 5-fluoro-2 ahydrodeoxyuridine [FdU]) are incorporated into DNA, perturbing its structure and generating Top1cc.

Purpose of the Study:

• To review the literature on Top1cc in mediating DNA damage and cytotoxicity of nucleoside analogs.
• To summarize differences between Top1cc induced by nucleoside analogs and camptothecins (CPTs), especially concerning DNA repair.
• To provide an overview of evolving research on targeting Top1 with nucleoside analogs for cancer treatment.

Main Methods:

• Literature review of studies on Top1cc, nucleoside analogs, and DNA repair pathways.
• Analysis of mechanisms by which nucleoside analogs induce Top1cc.
• Comparison of Top1cc induced by nucleoside analogs versus CPTs.

Main Results:

• Nucleoside analogs like FdU induce Top1cc, contributing to their DNA damaging and cytotoxic effects.
• Top1cc generated by nucleoside analogs differ from those induced by CPTs, particularly in DNA repair responses.
• Top1 poisons and nucleoside analogs, often combined with other agents like cisplatin, induce replication stress.

Conclusions:

• Top1 is a common target for both CPTs and nucleoside analogs, but these agents are not redundant.
• Distinct DNA repair pathways modulate the cytotoxic activities of Top1-targeting agents.
• Targeting Top1 with nucleoside analogs holds promise for more effective cancer therapy, especially when combined with other drugs and as replication stress inducers.