Mechanism of action of camptothecin

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

Research output: Contribution to journalArticle

336 Citations (Scopus)

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

Fingerprint

Camptothecin
DNA Damage
Tumors
DNA
Repair
Cells
Sumoylation
Reaction intermediates
Type I DNA Topoisomerase
Transcription
Cytotoxicity
Ubiquitin
S Phase
Machinery
Neoplasms
Down-Regulation
Chemical activation
Degradation
Killing
Damage

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.

Mechanism of action of camptothecin. / Liu, Leroy-Fong; Desai, S. D.; Li, T. K.; Mao, Y.; Sun, M.; Sim, S. P.

In: Annals of the New York Academy of Sciences, Vol. 922, 2000, p. 1-10.

Research output: Contribution to journalArticle

Liu, L-F, Desai, SD, Li, TK, Mao, Y, Sun, M & Sim, SP 2000, 'Mechanism of action of camptothecin', Annals of the New York Academy of Sciences, vol. 922, pp. 1-10.
Liu L-F, Desai SD, Li TK, Mao Y, Sun M, Sim SP. Mechanism of action of camptothecin. Annals of the New York Academy of Sciences. 2000;922:1-10.
Liu, Leroy-Fong ; Desai, S. D. ; Li, T. K. ; Mao, Y. ; Sun, M. ; Sim, S. P. / Mechanism of action of camptothecin. In: Annals of the New York Academy of Sciences. 2000 ; Vol. 922. pp. 1-10.
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