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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4276-4284. Prepublished online as a Blood First Edition Paper on February 12, 2004; DOI 10.1182/blood-2003-11-3825. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-11-3825v1 103/11/4276    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 Banker, D. E. Search for Related Content PubMed PubMed Citation Articles by Walter, R. B. Articles by Banker, D. E. Related Collections Neoplasia Apoptosis Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin Roland B. Walter, Brian W. Raden, Michelle R. Cronk, Irwin D. Bernstein, Frederick R. Appelbaum, and Deborah E. Banker From the Clinical Research Division, Fred Hutchinson Cancer Research Center; the Department of Pediatrics, University of Washington; and the Department of Medicine, University of Washington, Seattle, WA. The antibody-targeted therapeutic, gemtuzumab ozogamicin (GO, Mylotarg), is approved for treatment of relapsed acute myeloid leukemia (AML). We previously showed that AML blasts from GO refractory patients frequently express the drug transporters P-glycoprotein (Pgp) and/or multidrug resistance protein (MRP). We also previously reported that inhibition of drug transport by the Pgp modulator, cyclosporine A (CSA), can increase GO sensitivity in Pgp+ AML cells and that the peripheral benzodiazepine receptor ligand, PK11195, sensitizes AML cells to standard chemotherapeutics both by inhibiting Pgp-mediated efflux and by promoting mitochondrial apoptosis. We now show that PK11195 also can overcome multiple resistance mechanisms to increase GO sensitivity in AML cells, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases GO cytotoxicity in AML cells from many different cell lines and primary patient samples, often more effectively than CSA. We also show that PK11195 is nontoxic in NOD/SCID mice and can sensitize xenografted human AML cells to GO. Since PK11195 is well tolerated in humans as a single agent, its further study as a multifunctional chemosensitizer for anti-AML therapies, including GO-based therapies, is warranted. (Blood. 2004;103:4276-4284) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Chevallier, J. Delaunay, P. Turlure, A. Pigneux, M. Hunault, R. Garand, T. Guillaume, H. Avet-Loiseau, N. Dmytruk, S. Girault, et al. Long-Term Disease-Free Survival After Gemtuzumab, Intermediate-Dose Cytarabine, and Mitoxantrone in Patients With CD33+ Primary Resistant or Relapsed Acute Myeloid Leukemia J. Clin. Oncol., November 10, 2008; 26(32): 5192 - 5197. [Abstract] [Full Text] [PDF] 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, B. W. Raden, R. Zeng, P. Hausermann, I. D. Bernstein, and J. A. Cooper ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2 J. Leukoc. Biol., January 1, 2008; 83(1): 200 - 211. [Abstract] [Full Text] [PDF] A. F. Santidrian, A. M. Cosialls, L. Coll-Mulet, D. Iglesias-Serret, M. de Frias, D. M. Gonzalez-Girones, C. Campas, A. Domingo, G. Pons, and J. Gil The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells Haematologica, December 1, 2007; 92(12): 1631 - 1638. [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] 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]

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