Topoisomerase poisoning activity of novel disaccharide anthracyclines
| Autor: | Yves Pommier, Stefano Manzini, Stella Tinelli, Glenda Kohlhagen, Fabio Animati, Philippe Pourquier, Giovanni Capranico, Mario Bigioni, Monica Binaschi, Fulvio Guano, Franco Zunino |
|---|---|
| Přispěvatelé: | Pourquier, Philippe, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Laboratory of Molecular Pharmacology, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM) |
| Jazyk: | angličtina |
| Rok vydání: | 1999 |
| Předmět: |
Anthracycline
[SDV]Life Sciences [q-bio] Molecular Sequence Data Saccharomyces cerevisiae Pharmacology Biology 03 medical and health sciences 0302 clinical medicine In vivo medicine Idarubicin Humans Topoisomerase II Inhibitors Doxorubicin Cytotoxicity 030304 developmental biology 0303 health sciences Antibiotics Antineoplastic Base Sequence Topoisomerase Rational design In vitro 3. Good health [SDV] Life Sciences [q-bio] Biochemistry Carbohydrate Sequence 030220 oncology & carcinogenesis biology.protein Molecular Medicine Topoisomerase I Inhibitors Cell Division medicine.drug |
| Zdroj: | Molecular Pharmacology Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 1999, 56 (1), pp.77-84. ⟨10.1124/mol.56.1.77⟩ Scopus-Elsevier ResearcherID |
| ISSN: | 0026-895X |
| Popis: | International audience; Doxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases IIalpha and IIbeta. Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases IIalpha and IIbeta. The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I. |
| Databáze: | OpenAIRE |
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