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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 29, 2003 Accepted March 12, 2004 Targeting the Multidrug Resistance-1 Transporter in AML: Molecular Regulation and Therapeutic Strategies Daruka Mahadevan* and Alan F List Arizona Cancer Center - Hem/Onc, University of Arizona, Tucson, AZ, USA The H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA * Corresponding author; email: dmahadevan{at}azcc.arizona.edu. The multidrug resistance1 (MDR1) gene product, P-glycoprotein (P-gp), and the multidrug resistance related proteins (MRPs) are members of the 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 gatekeepers, 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 III 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: S. W. Lane, D. T. Scadden, and D. G. Gilliland The leukemic stem cell niche: current concepts and therapeutic opportunities Blood, August 6, 2009; 114(6): 1150 - 1157. [Abstract] [Full Text] [PDF] J. E. Karp, K. Flatten, E. J. Feldman, J. M. Greer, D. A. Loegering, R. M. Ricklis, L. E. Morris, E. Ritchie, B. D. Smith, V. Ironside, et al. Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide Blood, May 14, 2009; 113(20): 4841 - 4852. [Abstract] [Full Text] [PDF] B. D. Shah and J. E. 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