ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia.
Blood
; 121(12): 2285-8, 2013 Mar 21.
Article
em En
| MEDLINE
| ID: mdl-23341542
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
/
Trombocitopenia
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Compostos Bicíclicos Heterocíclicos com Pontes
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Linfoma
Tipo de estudo:
Evaluation_studies
Limite:
Animals
Idioma:
En
Revista:
Blood
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Austrália