| Structure-activity studies of novobiocin analogs as modulators of the cytotoxicity of etoposide (VP-16). | |
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MedLine Citation:
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PMID: 11216669 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have previously reported that the antibiotic novobiocin enhanced the toxicity of the anticancer agent etoposide (VP-16) to several drug-sensitive and -resistant tumor cell lines. The increase in VP-16 cytotoxicity produced by novobiocin was not due to the combined effects of these agents on topoisomerase II, but to inhibition by novobiocin of VP-16 efflux, which in turn led to increased accumulation of VP-16 and increased formation of potentially lethal VP-16-stabilized topoisomerase II-DNA covalent complexes. We have now identified novobiocin analogs that are essentially equivalent to novobiocin as inhibitors of the activity of topoisomerase II, but that are more potent than novobiocin (a) as modulators of the cytotoxicity of VP-16 to WEHI-3B leukemia and A549 lung carcinoma cells and (b) in increasing VP-16 accumulation in these cell lines. Thus, removal of the sugar moiety of novobiocin to form novobiocic acid enhanced the potency of the antibiotic as a modulator of VP-16, whereas the substituted coumarin ring alone (U-7587) was devoid of VP-16 modulatory activity. Modifications of the side chain of novobiocin significantly influenced modulatory activity, with cyclonovobiocic acid, which was formed from novobiocic acid by acid-catalyzed cycloaddition, being the most active in enhancing the cytotoxicity of VP-16. The increased potency of novobiocic acid and cyclonovobiocic acid as modulators of VP-16 activity was achieved with no change from novobiocin in the capacity of these analogs to inhibit the catalytic activity of mammalian topoisomerase II, indicating a change in the specificity of these analogs. |
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Authors:
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G Rappa; K Shyam; A Lorico; O Fodstad; A C Sartorelli |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Oncology research Volume: 12 ISSN: 0965-0407 ISO Abbreviation: Oncol. Res. Publication Date: 2000 |
Date Detail:
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Created Date: 2001-02-16 Completed Date: 2001-04-12 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9208097 Medline TA: Oncol Res Country: United States |
Other Details:
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Languages: eng Pagination: 113-9 Citation Subset: IM |
Affiliation:
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Department of Tumor Biology, Norwegian Radium Hospital, Montebello, Oslo. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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physiology Adenosine Triphosphate / pharmacology Antineoplastic Agents, Phytogenic / pharmacology* DNA Topoisomerases, Type II / antagonists & inhibitors* Drug Synergism Enzyme Inhibitors / pharmacology* Etoposide / pharmacology* Humans Multidrug Resistance-Associated Proteins Novobiocin / pharmacology* Structure-Activity Relationship Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA-66739/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATP-Binding Cassette Transporters; 0/Antineoplastic Agents, Phytogenic; 0/Enzyme Inhibitors; 0/Multidrug Resistance-Associated Proteins; 303-81-1/Novobiocin; 33419-42-0/Etoposide; 56-65-5/Adenosine Triphosphate; EC 5.99.1.3/DNA Topoisomerases, Type II |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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