In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas.
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.
Mason
Kylie D
KD
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.
Vandenberg
Cassandra J
CJ
Scott
Clare L
CL
Wei
Andrew H
AH
Cory
Suzanne
S
Huang
David C S
DC
Roberts
Andrew W
AW
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
C501332:ABT-737; D001713:Biphenyl Compounds; D009153:Mutagens; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D013449:Sulfonamides; D003520:Cyclophosphamide