title: The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan.
abstract: OBJECTIVE
  The aim of this study is to investigate the antimyeloma activity of a novel Bcl-2 family inhibitor, ABT-737, in preclinical treatment of multiple myeloma.
  
  
  METHODS
  The antimyeloma activity of ABT-737 was evaluated in cultured myeloma cell lines and patient myeloma samples, and in a xenograft mouse myeloma model. Drug combination therapy using ABT-737 with other commonly used myeloma drugs was also investigated.
  
  
  RESULTS
  MY5 and JJN3 cell lines exhibited the most sensitivity to ABT-737 with an EC(50) of 0.2 and 0.5 micromol/L, respectively, with increased cell apoptosis and elevated activated caspase-3. We identified two distinct groups of myeloma patient samples that were either sensitive or resistant to the drug. Four of 15 patient bone marrow samples (27%) were highly sensitive to ABT-737 at doses of 0.25 and 0.5 micromol/L, which eliminated 80% to 90% of myeloma cells as a result of cellular apoptosis 3 days after drug treatment. ABT-737 showed a synergistic effect when combined with dexamethasone or melphalan in inducing myeloma cell death. Furthermore, the dexamethasone-resistant MM1(Dex)R myeloma cell line was highly sensitive to 0.2 micromol/L ABT-737. As determined by colony assay, little or no detectable toxicity to patient hematologic progenitor cells was observed at 1 micromol/L ABT-737. ABT-737 dose dependently suppressed tumor growth in a xenograft MY5 mouse model.
  
  
  CONCLUSIONS
  These studies show substantial antimyeloma activity of ABT-737 as a single agent or in combination with dexamethasone or melphalan and suggest a rationale for future clinical trials.
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, 620 University Avenue, Toronto, Ontario, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Shu
authors.forename: Sheng-Ben
authors.initials: SB
authors.lastname: Liang
authors.forename: Young
authors.initials: Y
authors.lastname: Trieu
authors.forename: Donna
authors.initials: D
authors.lastname: Reece
authors.forename: Josh
authors.initials: J
authors.lastname: Paterson
authors.forename: Dingyan
authors.initials: D
authors.lastname: Wang
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D015850:Interleukin-6; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D003907:Dexamethasone; D008558:Melphalan