Targeting Topoisomerase I in the Era of Precision Medicine.

Abstract

Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. Because of their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecins are also widely used to elucidate the DNA repair pathways associated with DNA-protein cross-links and replication stress. This review summarizes the basic molecular mechanisms of action of TOP1 inhibitors, their current use, and limitations as anticancer agents. We introduce new therapeutic strategies based on novel TOP1 inhibitor chemical scaffolds including the indenoisoquinolines LMP400 (indotecan), LMP776 (indimitecan), and LMP744, and on tumor-targeted delivery TOP1 inhibitors using liposome, PEGylation, and antibody-drug conjugates. We also address how tumor-specific determinants such as homologous recombination defects (HRD and BRCAness) and Schlafen 11 (SLFN11) expression can be used to guide clinical application of TOP1 inhibitors in combination with DNA damage response inhibitors including PARP, ATR, CHEK1, and ATM inhibitors.

• Authors: Anish Thomas, Yves Pommier
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 22 Pg. 6581-6589 (11 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31227499 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Review)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Benzimidazoles
• Poly(ADP-ribose) Polymerase Inhibitors
• Topoisomerase I Inhibitors
• veliparib
• Irinotecan
• Topotecan
• DNA Topoisomerases, Type I

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzimidazoles (administration & dosage, adverse effects, therapeutic use)
• DNA Topoisomerases, Type I (metabolism)
• Humans
• Irinotecan (administration & dosage, adverse effects, therapeutic use)
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy, enzymology)
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Precision Medicine (methods)
• Topoisomerase I Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Topotecan (administration & dosage, adverse effects, therapeutic use)