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Blood, 1 October 2004, Vol. 104, No. 7, pp. 1940-1951. Prepublished online as a Blood First Edition Paper on June 24, 2004; DOI 10.1182/blood-2003-07-2490. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2490v1 104/7/1940    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mahadevan, D. Articles by List, A. F. Search for Related Content PubMed PubMed Citation Articles by Mahadevan, D. Articles by List, A. F. Related Collections Neoplasia Gene Expression Reviews in Translational Hematology Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  REVIEW IN TRANSLATIONAL HEMATOLOGY Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies Daruka Mahadevan, and Alan F. List From the The Arizona Cancer Center, Tucson; and The H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Abstract The multidrug resistance-1 (MDR1) gene product, P-glycoprotein (P-gp), and the multidrug resistance–related proteins (MRPs) are members of the adenosine triphosphate (ATP)–binding cassette (ABC) transporter gene superfamily that regulates the trafficking of drugs, peptides, ions, and xenobiotics across cell membrane barriers. Three-dimensional modeling of human MDR1/P-gp indicates that these glycoproteins function as efficient, ATP-dependent gate-keepers, which scan the plasma membrane and its inner leaflet to flip lipophilic substrates to the outer membrane leaflet. Delineation of the adverse prognostic power of MDR1 in adult acute myeloid leukemia (AML) raised hopes that pharmacologic blockade of P-gp would improve the outcome of conventional cytotoxic therapy, perhaps more so than in any other human malignancy. Phase 3 clinical trials investigating first- and second-generation P-gp antagonists have yielded conflicting results, emphasizing the importance of applying preclinical principals to realistically appraise expectations for clinical benefit. Structure-based design strategies and the delineation of transcriptional regulators of survival gene cassettes promise to yield novel, more-effective strategies to overcome drug resistance. Lessons learned from investigations of these and other mechanisms of cellular defense hold promise for a renaissance in the development of targeted therapeutics in acute leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Langer, M. D. Radmacher, A. S. Ruppert, S. P. Whitman, P. Paschka, K. Mrozek, C. D. Baldus, T. Vukosavljevic, C.-G. Liu, M. E. Ross, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study Blood, June 1, 2008; 111(11): 5371 - 5379. [Abstract] [Full Text] [PDF] I. L. K. Wong, K.-F. Chan, B. A. Burkett, Y. Zhao, Y. Chai, H. Sun, T. H. Chan, and L. M. C. Chow Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium Stiboglucanate Resistance in Leishmania Antimicrob. Agents Chemother., March 1, 2007; 51(3): 930 - 940. [Abstract] [Full Text] [PDF] L. M. Huff, J.-S. Lee, R. W. Robey, and T. Fojo Characterization of Gene Rearrangements Leading to Activation of MDR-1 J. Biol. Chem., December 1, 2006; 281(48): 36501 - 36509. [Abstract] [Full Text] [PDF] B. I. Sikic Multidrug resistance and stem cells in acute myeloid leukemia. Clin. Cancer Res., June 1, 2006; 12(11): 3231 - 3232. [Full Text] [PDF] M. H.G.P. Raaijmakers, E. P.L.M. de Grouw, B. A. van der Reijden, T. J.M. de Witte, J. H. Jansen, and R. A.P. Raymakers ABCB1 Modulation Does Not Circumvent Drug Extrusion from Primitive Leukemic Progenitor Cells and May Preferentially Target Residual Normal Cells in Acute Myelogenous Leukemia. Clin. Cancer Res., June 1, 2006; 12(11): 3452 - 3458. [Abstract] [Full Text] [PDF] P. J. Bastian, J. Ellinger, A. Wellmann, N. Wernert, L. C. Heukamp, S. C. Muller, and A. von Ruecker Diagnostic and Prognostic Information in Prostate Cancer with the Help of a Small Set of Hypermethylated Gene Loci Clin. Cancer Res., June 1, 2005; 11(11): 4097 - 4106. [Abstract] [Full Text] [PDF] M. Pallis, J. Fisher, L. Truran, M. Grundy, N. Russell, and A. Burnett Reproducible measurements of AML blast p-glycoprotein function in 2 center analyses Blood, February 1, 2005; 105(3): 1367 - 1368. [Full Text] [PDF]

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