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

Mason, KD; Vandenberg, CJ; Scott, CL; Wei, AH; Cory, S; Huang, DCS; Roberts, AW

Author(s): Mason, KD; Vandenberg, CJ; Scott, CL; Wei, AH; Cory, S; Huang, DCS; Roberts, AW;
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
Publisher's Version: https://doi.org/10.1073/pnas.0809957105
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Creation Date: 2008-11-18 12:00:00