title: ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia.
abstract: BH3-only proteins trigger the stress apoptosis pathway and chemical mimetics have great potential for cancer therapy. BH3-only proteins inhibit antiapoptotic members of the Bcl-2 family. Promising BH3 mimetic ABT-737 and the related orally available compound ABT-263 (navitoclax) bind avidly to antiapoptotic Bcl-2, Bcl-xL, and Bcl-w. However, their interaction with Bcl-xL provokes thrombocytopenia, which has proven to be the dose-limiting toxicity. We have tested the efficacy of ABT-199, a new Bcl-2-specific BH3 mimetic, against aggressive progenitor cell lymphomas derived from bitransgenic myc/bcl-2 mice. As a single agent, ABT-199 was as effective as ABT-737 in prolonging survival of immunocompetent tumor-bearing mice without causing thrombocytopenia. Both drugs acted rapidly but, contrary to prevailing models, their apoptotic activity did not rely upon the BH3-only protein Bim. When ABT-737 was combined with the proteosome inhibitor bortezomib or CDK inhibitor purvalanol, many treated animals achieved long-term remission.
authors: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
authors: Cassandra J
authors: CJ
authors: Vandenberg
authors: Suzanne
authors: S
authors: Cory
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D032701:Biomimetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016259:Genes, myc / Q000502:physiology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D013379:Substrate Specificity; D013449:Sulfonamides / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D019086:Bridged Bicyclo Compounds, Heterocyclic; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax