Mechanism of action of camptothecin

Ann N Y Acad Sci. 2000;922:1-10. doi: 10.1111/j.1749-6632.2000.tb07020.x.

Abstract

Camptothecin (CPT) class of compounds has been demonstrated to be effective against a broad spectrum of tumors. Their molecular target has been firmly established to be human DNA topoisomerase I (topo I). CPT inhibits topo I by blocking the rejoining step of the cleavage/religation reaction of topo-I, resulting in accumulation of a covalent reaction intermediate, the cleavable complex. The primary mechanism of cell killing by CPT is S-phase-specific killing through potentially lethal collisions between advancing replication forks and topo-I cleavable complexes. Collisions with the transcription machinery have also been shown to trigger the formation of long-lived covalent topo-I DNA complexes, which contribute to CPT cytotoxicity. Two novel repair responses to topo-I-mediated DNA damage involving covalent modifications of topo-I have been discovered. The first involves activation of the ubiquitin/26S proteasome pathway, leading to degradation of topo-I (CPT-induced topo-I downregulation). The second involves SUMO conjugation to topo-I. The potentials roles of these new mechanisms for repair of topo-I-mediated DNA damage in determining CPT sensitivity/resistance in tumor cells are discussed.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Camptothecin / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Intercalating Agents / pharmacology
  • Topoisomerase I Inhibitors

Substances

  • Antineoplastic Agents, Phytogenic
  • Enzyme Inhibitors
  • Intercalating Agents
  • Topoisomerase I Inhibitors
  • Camptothecin