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The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by indolocarbazoles.
Biochemistry. 1999 Jul 06; 38(27):8605-11.B

Abstract

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.

Authors+Show Affiliations

Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, U-524 INSERM, IRCL, Lille, France. bailly@lille.inserm.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10393535

Citation

Bailly, C, et al. "The Camptothecin-resistant Topoisomerase I Mutant F361S Is Cross-resistant to Antitumor Rebeccamycin Derivatives. a Model for Topoisomerase I Inhibition By Indolocarbazoles." Biochemistry, vol. 38, no. 27, 1999, pp. 8605-11.
Bailly C, Carrasco C, Hamy F, et al. The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by indolocarbazoles. Biochemistry. 1999;38(27):8605-11.
Bailly, C., Carrasco, C., Hamy, F., Vezin, H., Prudhomme, M., Saleem, A., & Rubin, E. (1999). The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by indolocarbazoles. Biochemistry, 38(27), 8605-11.
Bailly C, et al. The Camptothecin-resistant Topoisomerase I Mutant F361S Is Cross-resistant to Antitumor Rebeccamycin Derivatives. a Model for Topoisomerase I Inhibition By Indolocarbazoles. Biochemistry. 1999 Jul 6;38(27):8605-11. PubMed PMID: 10393535.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by indolocarbazoles. AU - Bailly,C, AU - Carrasco,C, AU - Hamy,F, AU - Vezin,H, AU - Prudhomme,M, AU - Saleem,A, AU - Rubin,E, PY - 1999/7/7/pubmed PY - 1999/7/7/medline PY - 1999/7/7/entrez SP - 8605 EP - 11 JF - Biochemistry JO - Biochemistry VL - 38 IS - 27 N2 - 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. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/10393535/The_camptothecin_resistant_topoisomerase_I_mutant_F361S_is_cross_resistant_to_antitumor_rebeccamycin_derivatives__A_model_for_topoisomerase_I_inhibition_by_indolocarbazoles_ L2 - https://doi.org/10.1021/bi983052y DB - PRIME DP - Unbound Medicine ER -