Document Detail


Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells.
MedLine Citation:
PMID:  14641819     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Norman J Lacayo; George E Duran; Branimir I Sikic
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of experimental therapeutics & oncology     Volume:  3     ISSN:  1359-4117     ISO Abbreviation:  J. Exp. Ther. Oncol.     Publication Date:    2003 May-Jun
Date Detail:
Created Date:  2003-12-03     Completed Date:  2004-03-12     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9604933     Medline TA:  J Exp Ther Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  127-35     Citation Subset:  IM    
Affiliation:
Oncology Division, Department of Medicine, Stanford University School of Medicine, CA 94305-5151, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / 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:
R01 CA 52186/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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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