title: Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo.
abstract: Defects in apoptosis signaling contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), and overexpression of antiapoptotic Bcl-2 (Bcl-2 and Bcl-X(L)) 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.
authors.affiliation: Developmental Therapeutics Program, Childrens Hospital Los Angeles and University of Southern California Institute for Pediatric Clinical Research, Los Angeles, CA 90027, USA. mkang@chla.usc.edu
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Kang
authors.forename: Barbara
authors.initials: B
authors.lastname: Szymanska
authors.forename: Urszula
authors.initials: U
authors.lastname: Wilczynska-Kalak
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sheard
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Harned
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001215:Asparaginase / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002648:Child; D045304:Cytochromes c / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D015996:Survival Rate; D014750:Vincristine / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014750:Vincristine; D003907:Dexamethasone; D045304:Cytochromes c; D001215:Asparaginase