Cancer Research Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine  Joint Metastasis Research Society-AACR Conference on Metastasis
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Cancer Research 67, 262-268, January 1, 2007. doi: 10.1158/0008-5472.CAN-06-2680
© 2007 American Association for Cancer Research

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Experimental Therapeutics, Molecular Targets, and Chemical Biology

Multidrug Resistance Protein 4 Protects Bone Marrow, Thymus, Spleen, and Intestine from Nucleotide Analogue–Induced Damage

Martin G. Belinsky1, Ping Guo3, Kun Lee1, Feng Zhou3, Elena Kotova1, Alex Grinberg4, Heiner Westphal4, Irina Shchaveleva1, Andres Klein-Szanto2, James M. Gallo3 and Gary D. Kruh1

1 Medical Science Division, 2 Department of Pathology, Fox Chase Cancer Center, 3 Temple University School of Pharmacy, Philadelphia, Pennsylvania; and 4 National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

Requests for reprints: Gary D. Kruh, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-5317; Fax: 215-728-3603; E-mail: gary.kruh{at}fccc.edu.

Nucleoside-based analogues are mainstays in the treatment of cancer, viral infections, and inflammatory diseases. Recent studies showing that the ATP-binding cassette transporter, multidrug resistance protein 4, is able to efflux nucleoside and nucleotide analogues from transfected cells suggests that the pump may affect the efficacy of this class of agents. However, the in vivo pharmacologic functions of the pump are largely unexplored. Here, using Mrp4–/– mice as a model system, and the nucleotide analogue, 9'-(2'-phosphonylmethoxyethyl)-adenine (PMEA) as a probe, we investigate the ability of Mrp4 to function in vivo as an endogenous resistance factor. In the absence of alterations in plasma PMEA levels, Mrp4-null mice treated with PMEA exhibit increased lethality associated with marked toxicity in several tissues. Affected tissues include the bone marrow, spleen, thymus, and gastrointestinal tract. In addition, PMEA penetration into the brain is increased in Mrp4–/– mice. These findings indicate that Mrp4 is an endogenous resistance factor, and that the pump may be a component of the blood-brain barrier for nucleoside-based analogues. This is the first demonstration that an ATP-binding cassette transporter can affect in vivo tissue sensitivity towards this class of agents. [Cancer Res 2007;67(1):262–8]




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2007 by the American Association for Cancer Research.