Mechanism of Action of Camptothecin

Liu, L.F. and Shyamal D., Desai and Li, Tsai-Kun and Mao, Yong and Mei, Sun and Sim, S.P (2006) Mechanism of Action of Camptothecin. Annals of New York Academy of Science, 922. ISSN 1749-6632

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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.

Item Type: Article
Uncontrolled Keywords: Camptothecin, topoisomerase I (topo I), unimas, university, universiti, Borneo, Malaysia, Sarawak, Kuching, Samarahan, ipta, education, research, Universiti Malaysia Sarawak
Subjects: R Medicine > R Medicine (General)
Divisions: Academic Faculties, Institutes and Centres > Faculty of Medicine and Health Sciences
Depositing User: Karen Kornalius
Date Deposited: 03 Jul 2015 02:52
Last Modified: 03 Jul 2015 02:52

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