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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2057-2066. Prepublished online as a Blood First Edition Paper on May 29, 2007; DOI 10.1182/blood-2007-03-080325. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-03-080325v1 110/6/2057    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 Kang, M. H. Articles by Reynolds, C. P. Search for Related Content PubMed PubMed Citation Articles by Kang, M. H. Articles by Reynolds, C. P. Related Collections Neoplasia Apoptosis Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo Min H. Kang1, Yun Hee Kang1, Barbara Szymanska2, Urszula Wilczynska-Kalak2, Michael A. Sheard1, Theresa M. Harned1, Richard B. Lock2, and C. Patrick Reynolds1 1 Developmental Therapeutics Program, Childrens Hospital Los Angeles and University of Southern California (USC-CHLA) Institute for Pediatric Clinical Research, Los Angeles, CA; 2 Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia Defects in apoptosis signaling contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), and overexpression of antiapoptotic Bcl-2 (Bcl-2 and Bcl-XL) family proteins has been observed in ALL. ABT-737 is a small-molecule BH3-mimetic that inhibits the antiapoptotic Bcl-2 family proteins. We evaluated the cytotoxicity of ABT-737 in combination with vincristine, dexamethasone, and L-asparaginase (VXL) in 7 ALL cell lines. Multilog synergistic cytotoxicity was observed in all 7 cell lines with ABT-737 plus L-asparaginase or vincristine, and in 5 of 7 cell lines with ABT-737 plus dexamethasone or VXL. In leukemia cells, but not in normal lymphocytes, ABT-737 plus L-asparaginase induced greater mitochondrial depolarization (JC-1 staining); mitochondrial cytochrome c release; activation of Bax, Bid, and caspases (immunoblotting); and eventually apoptosis (annexin V staining) than did either drug alone. In mouse xenografts derived from patients with ALL at diagnosis (ALL-7) or at relapse (ALL-19), event-free survival (EFS) was significantly enhanced with ABT-737 plus VXL relative to VXL or ABT-737 alone (P .02). Thus, ABT-737 synergistically enhanced VXL cytotoxicity in ALL cell lines via a mitochondrial death pathway and enhanced EFS in VXL-treated mice bearing ALL xenografts. Combining VXL with a BH3-mimetic warrants clinical investigation in ALL at relapse and potentially in chemotherapy-resistant ALL subgroups. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Li, Y. Zang, C. Li, N. S. Patel, J. R. Grandis, and D. E. Johnson ABT-737 Synergizes with Chemotherapy to Kill Head and Neck Squamous Cell Carcinoma Cells via a Noxa-Mediated Pathway Mol. Pharmacol., May 1, 2009; 75(5): 1231 - 1239. [Abstract] [Full Text] [PDF] M. H. Kang and C. P. Reynolds Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy Clin. Cancer Res., February 15, 2009; 15(4): 1126 - 1132. [Abstract] [Full Text] [PDF] K. D. Mason, C. J. Vandenberg, C. L. Scott, A. H. Wei, S. Cory, D. C. S. Huang, and A. W. Roberts In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas PNAS, November 18, 2008; 105(46): 17961 - 17966. [Abstract] [Full Text] [PDF] O. Kutuk and A. Letai Alteration of the Mitochondrial Apoptotic Pathway Is Key to Acquired Paclitaxel Resistance and Can Be Reversed by ABT-737 Cancer Res., October 1, 2008; 68(19): 7985 - 7994. [Abstract] [Full Text] [PDF] A. R. Shoemaker, M. J. Mitten, J. Adickes, S. Ackler, M. Refici, D. Ferguson, A. Oleksijew, J. M. O'Connor, B. Wang, D. J. Frost, et al. Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models Clin. Cancer Res., June 1, 2008; 14(11): 3268 - 3277. [Abstract] [Full Text] [PDF] C. Tse, A. R. Shoemaker, J. Adickes, M. G. Anderson, J. Chen, S. Jin, E. F. Johnson, K. C. Marsh, M. J. Mitten, P. Nimmer, et al. ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor Cancer Res., May 1, 2008; 68(9): 3421 - 3428. [Abstract] [Full Text] [PDF] M. H. Kang, Z. Wan, Y. H. Kang, R. Sposto, and C. P. Reynolds Mechanism of Synergy of N-(4-Hydroxyphenyl)Retinamide and ABT-737 in Acute Lymphoblastic Leukemia Cell Lines: Mcl-1 Inactivation J Natl Cancer Inst, April 16, 2008; 100(8): 580 - 595. [Abstract] [Full Text] [PDF] D. S. Ziegler, A. L. Kung, and M. W. Kieran Anti-Apoptosis Mechanisms in Malignant Gliomas J. Clin. Oncol., January 20, 2008; 26(3): 493 - 500. [Abstract] [Full Text] [PDF]

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