喜树碱
拓扑替康
拓扑异构酶
化学
内酯
立体化学
细胞毒性
DNA
生物化学
体外
生物
遗传学
化疗
作者
Amélie Lansiaux,Stéphane Léonce,Laurence Kraus‐Berthier,Christine Bal-Mahieu,Romain Mazinghien,Sébastien Didier,Marie‐Hélène David‐Cordonnier,Patrick Hautefaye,Gilbert Lavielle,Christian Bailly,John A. Hickman,Alain St. Pierre
出处
期刊:Molecular Pharmacology
[American Society for Pharmacology and Experimental Therapeutics]
日期:2007-05-09
卷期号:72 (2): 311-319
被引量:30
标识
DOI:10.1124/mol.107.034637
摘要
The E-ring lactone is the Achilles9 heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T↓G sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC50 of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.
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