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

Defects in apoptosis signaling contribute to poor outcome in pediatric acute lym-phoblastic leukemia (ALL), and overex-pression 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, dexametha-sone, and L-asparaginase (VXL) in 7 ALL cell lines. Multilog synergistic cytotoxic-ity was observed in all 7 cell lines with ABT-737 plus L-asparaginase or vincris-tine, 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 re-lease; activation of Bax, Bid, and caspases (immunoblotting); and eventually apopto-sis (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 cytotoxic-ity 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 war-rants clinical investigation in ALL at re-lapse and potentially in chemotherapy