In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas
Details
Publication Year 2008-11-18,Volume 105,Issue #46,Page 17961-17966
Journal Title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type
Journal Article
Abstract
Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of cliff use 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 E mu-myc transgenic mice or E mu-myc mice that also expressed an E mu-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.
Publisher
NATL ACAD SCIENCES
Keywords
BH3 MIMETIC ABT-737; BURKITTS-LYMPHOMA; TRANSGENIC MICE; CHROMOSOME-TRANSLOCATION; HOMOZYGOUS DELETIONS; PROAPOPTOTIC GENE; INHIBITOR ABT-737; B-CELLS; APOPTOSIS; LEUKEMIA
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Creation Date: 2008-11-18 12:00:00
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