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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2003-02-0396. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-02-0396v1 102/4/1466    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 Walter, R. B. Articles by Linenberger, M. L. Search for Related Content PubMed PubMed Citation Articles by Walter, R. B. Articles by Linenberger, M. L. Related Collections Neoplasia Signal Transduction Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2003, Vol. 102, No. 4, pp. 1466-1473 NEOPLASIA Multidrug resistance protein attenuates gemtuzumab ozogamicin–induced cytotoxicity in acute myeloid leukemia cells Roland B. Walter, Brian W. Raden, Tom C. Hong, David A. Flowers, Irwin D. Bernstein, and Michael L. Linenberger From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and the Departments of Pediatrics and Medicine, University of Washington, Seattle. Gemtuzumab ozogamicin (GO) is a novel immunoconjugate therapy for acute myeloid leukemia (AML). P-glycoprotein (Pgp) confers resistance to GO and is associated with a worse clinical response. To address whether multidrug resistance protein (MRP) affects GO susceptibility, we characterized Pgp, MRP1, and MRP2 expression in CD33+ cell lines and CD33+ AML samples and analyzed the effect of the Pgp inhibitor cyclosporine (CSA) and the MRP inhibitor MK-571 on GO-induced cytotoxicity. MRP1, but not MRP2, expression correlated with MRP activity. MK-571 enhanced GO-induced cytotoxicity in Pgpnegative/MRP-positive NB4 and HL-60 cells. CSA, but not MK-571 alone, restored GO susceptibility in Pgp-positive/MRP-positive TF1 cells; however, MK-571 enhanced cytotoxicity in the presence of CSA. All patient samples exhibited MRP activity, and 17 of 23 exhibited Pgp activity. CSA increased GO-induced cytotoxicity in 12 Pgp-positive samples, whereas MK-571 alone was effective in only one sample with minimal Pgp activity. In 3 Pgp-positive/MRP-positive samples, MK-571 enhanced GO-induced cytotoxicity in the presence of CSA. Thus, MRP1 may attenuate susceptibility to GO. This effect was comparatively less than that for Pgp and required the inhibition of Pgp for detection in cells that coexpressed both transporters. Because MK-571 and CSA failed to affect cytotoxicity in a portion of Pgp-positive/MRP-positive AML samples, additional resistance mechanisms are likely important. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. B. Walter, K. M. Boyle, F. R. Appelbaum, I. D. Bernstein, and J. M. Pagel Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenografts Blood, May 1, 2008; 111(9): 4813 - 4816. [Abstract] [Full Text] [PDF] R. B. Walter, T. A. Gooley, V. H. J. van der Velden, M. R. Loken, J. J. M. van Dongen, D. A. Flowers, I. D. Bernstein, and F. R. Appelbaum CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy Blood, May 15, 2007; 109(10): 4168 - 4170. [Abstract] [Full Text] [PDF] S. B. Le, M. K. Hailer, S. Buhrow, Q. Wang, K. Flatten, P. Pediaditakis, K. C. Bible, L. D. Lewis, E. A. Sausville, Y.-P. Pang, et al. Inhibition of Mitochondrial Respiration as a Source of Adaphostin-induced Reactive Oxygen Species and Cytotoxicity J. Biol. Chem., March 23, 2007; 282(12): 8860 - 8872. [Abstract] [Full Text] [PDF] R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF] R. B. Walter, J. L. Pirga, M. R. Cronk, S. Mayer, F. R. Appelbaum, and D. E. Banker PK11195, a peripheral benzodiazepine receptor (pBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a pBR-independent, direct transporter-modulating mechanism Blood, November 15, 2005; 106(10): 3584 - 3593. [Abstract] [Full Text] [PDF] R. B. Walter, B. W. Raden, D. M. Kamikura, J. A. Cooper, and I. D. Bernstein Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity Blood, February 1, 2005; 105(3): 1295 - 1302. [Abstract] [Full Text] [PDF] R. B. Walter, B. W. Raden, M. R. Cronk, I. D. Bernstein, F. R. Appelbaum, and D. E. Banker The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin Blood, June 1, 2004; 103(11): 4276 - 4284. [Abstract] [Full Text] [PDF]

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