Targeting Topoisomerase I in the Era of Precision Medicine

Clin Cancer Res. 2019 Nov 15;25(22):6581-6589. doi: 10.1158/1078-0432.CCR-19-1089. Epub 2019 Jun 21.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

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

Substances

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