The Camptothecin-Resistant Topoisomerase I Mutant F361S Is Cross-Resistant to Antitumor Rebeccamycin Derivatives. A Model for Topoisomerase I Inhibition by Indolocarbazoles

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• 作者：Christian Bailly ; Carolina Carrasco ; Franç ; ois Hamy ; Hervé ; Vezin ; Michelle Prudhomme ; Ahamed Saleem ; and Eric Rubin
• 刊名：Biochemistry
• 出版年：1999
• 出版时间：July 6, 1999
• 年：1999
• 卷：38
• 期：27
• 页码：8605 - 8611
• 全文大小：195K
• 年卷期：v.38,no.27(July 6, 1999)
• ISSN：1520-4995

文摘

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 Iclinical trials. We have investigated the mechanism of topoisomerase I inhibition by a rebeccamycinanalogue, 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 inhibitionby camptothecin (CPT). Here we show that the mutated enzyme is cross-resistant to the rebeccamycinanalogue. Despite their profound structural differences, CPT and R-3 interfere similarly with the activityof the wild-type and mutant topoisomerase I enzymes, and the drug-induced cleavable complexes areequally sensitive to the NaCl concentration. CPT and IND likely recognize identical structural elementsof 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 showingthat CPT and IND share common steric and electronic features is proposed. The model helps to identifya specific pharmacophore for topoisomerase I inhibitors.