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    Cancer Res. 2009 Aug 15;69(16):6396-404. Epub 2009 Aug 4.

    Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer.

    Pajic M, Iyer JK, Kersbergen A, van der Burg E, Nygren AO, Jonkers J, Borst P, Rottenberg S.

    Source

    Division of Molecular Biology and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

    Abstract

    We have found previously that acquired doxorubicin resistance in a genetically engineered mouse model for BRCA1-related breast cancer was associated with increased expression of the mouse multidrug resistance (Mdr1) genes, which encode the drug efflux transporter ATP-binding cassette B1/P-glycoprotein (P-gp). Here, we show that even moderate increases of Mdr1 expression (as low as 5-fold) are sufficient to cause doxorubicin resistance. These moderately elevated tumor P-gp levels are below those found in some normal tissues, such as the gut. The resistant phenotype could be completely reversed by the third-generation P-gp inhibitor tariquidar, which provides a useful strategy to circumvent this type of acquired doxorubicin resistance. The presence of MDR1A in drug-resistant tumors with a moderate increase in Mdr1a transcripts could be shown with a newly generated chicken antibody against a mouse P-gp peptide. Our data show the usefulness of realistic preclinical models to characterize levels of Mdr1 gene expression that are sufficient to cause resistance.

    PMID:
    19654309
    [PubMed - indexed for MEDLINE]
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