Mechanism of Action of Camptothecin

• Main Authors: Liu, L.F., Shyamal D., Desai, Li, Tsai-Kun, Mao, Yong, Mei, Sun, Sim, S.P
• Format: E-Article
• Published: Annals of the New York Academy of Sciences 2006
• Subjects: R Medicine (General)
• Online Access: http://ir.unimas.my/id/eprint/8233/; http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2000.tb07020.x/abstract;jsessionid=8077573930C275ADC499C4011810F5D6.f02t03?userIsAuthenticated=false&deniedAccessCustomisedMessage=

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.