Document Detail

Overexpression of the multidrug resistance-associated protein (MRP) gene in vincristine but not doxorubicin-selected multidrug-resistant murine erythroleukemia cells.
MedLine Citation:
PMID:  7923205     Owner:  NLM     Status:  MEDLINE    
Multidrug-resistant sublines of the murine erythroleukemia cell line PC4 were sequentially selected in increasing vincristine concentrations (5-160 ng/ml). The low- and intermediate-level resistant cell lines, selected in < or = 40 ng/ml of vincristine, demonstrated resistance to Vinca alkaloids and to an epipodophyllotoxin but little or none to an anthracycline. The expression of murine mdr genes, as analyzed by Northern blotting, revealed a baseline expression of murine mdr2 in parental cells that was unchanged in the drug-resistant cell lines. Overexpression of mdr3 was observed only in the highest-level resistant cell line, PC-V160, whereas mdr1 mRNA was not detected in any of the cell lines. The polymerase chain reaction, using mdr3-specific primers, excluded the possibility that low levels of P-glycoprotein expression contributed to the resistance phenotype in the low and intermediate-level resistant cell lines. Northern blot analysis using a human complementary DNA probe for the multidrug resistance-associated protein (MRP) demonstrated overexpression of murine mrp in each of the vincristine-selected sublines. Genomic amplification of the mrp gene was coincident with mrp overexpression. The expression of mrp was also examined in two series of previously characterized doxorubicin-selected cell lines derived from parental PC4 and C7D murine erythroleukemia cells. In contrast to the vincristine-selected cell lines, overexpression of mrp was not detected. These studies demonstrate that, in murine erythroleukemia cells selected for vincristine resistance, overexpression of murine mrp occurred prior to that for murine mdr. In contrast to human MRP, selection for vincristine, but not doxorubicin resistance, resulted in the overexpression of murine mrp.
C A Slapak; P M Fracasso; R L Martell; D L Toppmeyer; J M Lecerf; S B Levy
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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:  Cancer research     Volume:  54     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1994 Nov 
Date Detail:
Created Date:  1994-11-23     Completed Date:  1994-11-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5607-13     Citation Subset:  IM    
Center for Adaptation Genetics and Drug Resistance, Tufts University School of Medicine, Boston, MA 02111.
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MeSH Terms
Base Sequence
Doxorubicin / metabolism,  pharmacology*
Drug Resistance / genetics
Leukemia, Erythroblastic, Acute / genetics,  metabolism*,  pathology
Molecular Sequence Data
P-Glycoprotein / genetics,  metabolism*
Polymerase Chain Reaction
Tumor Cells, Cultured / drug effects
Vincristine / metabolism,  pharmacology*
Grant Support
Reg. No./Substance:
0/P-Glycoprotein; 23214-92-8/Doxorubicin; 57-22-7/Vincristine

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