Mechanism of Action of Camptothecin

Annals of the New York Academy of Sciences - Tập 922 Số 1 - Trang 1-10 - 2000
Leroy F. Liu1, Shyamal D. Desai1, Tsai‐Kun Li1, Yong Mao1, Mei Sun1, Sai-Peng Sim1
1Department of Pharmacology UMDNJ-Robert Wood Johnson Medical School Piscataway, New Jersey 08854 USA

Tóm tắt

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.

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