Mechanism of action of camptothecin.

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.

• Authors: L F Liu, S D Desai, T K Li, Y Mao, M Sun, S P Sim
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 922 Pg. 1-10 ( 2000) ISSN: 0077-8923 [Print] United States
• PMID: 11193884 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

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

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Camptothecin (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Intercalating Agents (pharmacology)
• Topoisomerase I Inhibitors