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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.

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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.


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