Mechanism of action of camptothecin

Leroy-Fong Liu, S. D. Desai, T. K. Li, Y. Mao, M. Sun, S. P. Sim

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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 potential roles of these new mechanisms for repair of topo-I-mediated DNA damage in determining CPT sensitivity/resistance in tumor cells are discussed.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalAnnals of the New York Academy of Sciences
Volume922
Publication statusPublished - 2000
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Liu, L-F., Desai, S. D., Li, T. K., Mao, Y., Sun, M., & Sim, S. P. (2000). Mechanism of action of camptothecin. Annals of the New York Academy of Sciences, 922, 1-10.