The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by indolocarbazoles

被引:29
作者
Bailly, C
Carrasco, C
Hamy, F
Vezin, H
Prudhomme, M
Saleem, A
Rubin, E
机构
[1] Ctr Oscar Lambret, Lab Pharmacol Antitumorale, F-59045 Lille, France
[2] IRCL, INSERM, U524, F-59045 Lille, France
[3] Novartis Pharma Inc, Pharma Res, CH-4002 Basel, Switzerland
[4] Chim Organ Phys Lab, CNRS, URA 351, F-59655 Villeneuve Dascq, France
[5] Univ Blaise Pascal, SEESIB, CNRS, UMR 6504, F-63177 Aubiere, France
[6] Canc Inst New Jersey, Dept Pharmacol, Piscataway, NJ 08854 USA
关键词
D O I
10.1021/bi983052y
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
DNA topoisomerase I is a major cellular target for antitumor indolocarbazole derivatives (IND) such as the antibiotic rebeccamycin and the synthetic analogue NB-506 which is undergoing phase I clinical trials. We have investigated the mechanism of topoisomerase I inhibition by a rebeccamycin analogue, R-3, using the wild-type human topoisomerase I and a well-characterized recombinant enzyme, F361S. The catalytic activity of this mutant remains fully intact, but the enzyme is resistant to inhibition by camptothecin (CPT). Here we show that the mutated enzyme is cross-resistant to the rebeccamycin analogue. Despite their profound structural differences, CPT and R-3 interfere similarly with the activity of the wild-type and mutant topoisomerase I enzymes, and the drug-induced cleavable complexes are equally sensitive to the NaCl concentration. CPT and IND likely recognize identical structural elements of the topoisomerase I-DNA covalent complex; however, differences do exist in terms of sequence-specificity of topoisomerase I-mediated DNA cleavage. For the first time, a molecular model showing that CPT and IND share common steric and electronic features is proposed. The model helps to identify a specific pharmacophore for topoisomerase I inhibitors.
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页码:8605 / 8611
页数:7
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