| Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells. | |
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MedLine Citation:
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PMID: 14641819 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Idarubicin (IDA) is an anthracycline anticancer drug utilized in the treatment of acute leukemias. There are conflicting data published with regard to the cross-resistance of IDA in multidrug-resistant (MDR) cells expressing P-glycoprotein (P-gp). We evaluated the cytotoxicity and cellular accumulation of IDA in a panel of anthracycline-selected MDR cell lines. Leukemia K562/R7 cells and sarcoma MES-SA/Dx5 cells expressing high levels of the MDR1 (ABCB1) gene were resistant to IDA (42-fold and 150-fold, respectively). In both of these cell lines, resistance to IDA was equivalent to that for doxorubicin, the drug used to select for the MDR variants. The P-gp inhibitor PSC 833 (valspodar) at 2 microM completely restored sensitivity to IDA. IDA accumulation was decreased 12-fold in MES-SA/Dx5 cells vs parental cell line, and drug uptake was restored to control levels by PSC 833. Reduced intracellular IDA was correlated with P-gp content by flow cytometry. Experiments in NIH3T3 murine cells transfected with the human MDR1 gene substantiated the findings of cross-resistance to IDA and reversal of resistance by PSC 833. Our data indicate that IDA is a high-affinity substrate for P-gp. |
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Authors:
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Norman J Lacayo; George E Duran; Branimir I Sikic |
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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: Journal of experimental therapeutics & oncology Volume: 3 ISSN: 1359-4117 ISO Abbreviation: J. Exp. Ther. Oncol. Publication Date: 2003 May-Jun |
Date Detail:
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Created Date: 2003-12-03 Completed Date: 2004-03-12 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9604933 Medline TA: J Exp Ther Oncol Country: United States |
Other Details:
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Languages: eng Pagination: 127-35 Citation Subset: IM |
Affiliation:
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Oncology Division, Department of Medicine, Stanford University School of Medicine, CA 94305-5151, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibiotics, Antineoplastic
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pharmacology*,
therapeutic use Cyclosporins / pharmacology*, therapeutic use Doxorubicin / pharmacology, therapeutic use Drug Resistance, Multiple Drug Resistance, Neoplasm Flow Cytometry Humans Idarubicin / pharmacology*, therapeutic use K562 Cells / drug effects* P-Glycoprotein / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA 52186/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Cyclosporins; 0/P-Glycoprotein; 121584-18-7/valspodar; 23214-92-8/Doxorubicin; 58957-92-9/Idarubicin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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