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Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17961-6. doi: 10.1073/pnas.0809957105. Epub 2008 Nov 11.

In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas.

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1
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.

Abstract

Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x(L), and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Emu-myc transgenic mice or Emu-myc mice that also expressed an Emu-bcl-2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc/bcl-2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc/bcl-2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.

PMID:
19004807
PMCID:
PMC2582212
DOI:
10.1073/pnas.0809957105
[Indexed for MEDLINE]
Free PMC Article
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