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: Cassandra J Vandenberg, Suzanne Cory
• Journal: Blood (Blood) Vol. 121 Issue 12 Pg. 2285-8 (Mar 21 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23341542 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bax protein (53-86)
• Bridged Bicyclo Compounds, Heterocyclic
• Peptide Fragments
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• venetoclax

Topics

• Animals
• Antineoplastic Agents (adverse effects, pharmacology, therapeutic use)
• Biomimetics
• Bridged Bicyclo Compounds, Heterocyclic (adverse effects, pharmacology, therapeutic use)
• Cell Transformation, Neoplastic (genetics)
• Genes, myc (physiology)
• Lymphoma (drug therapy, genetics, mortality, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasm Invasiveness
• Peptide Fragments (pharmacology)
• Proto-Oncogene Proteins (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics)
• Substrate Specificity
• Sulfonamides (adverse effects, pharmacology, therapeutic use)
• Survival Analysis
• Thrombocytopenia (chemically induced, epidemiology, prevention & control)
• Treatment Outcome