The Bcl-2 Family Protein Inhibitor, ABT-737, Has Substantial Antimyeloma Activity and Shows Synergistic Effect with Dexamethasone and Melphalan

Suzanne Trudel, A. Keith Stewart, Zhihua Li, Yanjun Shu, Sheng-Ben Liang, Young Trieu, Donna Reece, Josh Paterson, Dingyan Wang, Xiao-Yan Wen
2007 Clinical Cancer Research  
Purpose: 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. Experimental Design: 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
more » ... to ABT-737 with an EC 50 of 0.2 and 0.5 Amol/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 Amol/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 Amol/L ABT-737. As determined by colony assay, little or no detectable toxicity to patient hematologic progenitor cells was observed at 1 Amol/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. Downloaded from Fig. 2. Efficacy of ABT-737 in inducing apoptosis of cultured myeloma cell lines. Nine myeloma cell lines were treated with various doses of ABT-737 for 48 h in culture. (A) MTTassay was done to determine cell viability (left), and the EC 50 values of ABT-737 in all the nine cell lines were calculated (right). MY5 and JJN3 were most sensitive to ABT-737 associated with increased cell apoptosis as determined by Annexin V staining (B) and increased activated caspase-3 (C). PE, phycoerythrin.
doi:10.1158/1078-0432.ccr-06-1526 pmid:17255285 fatcat:4xrygjcvijaorp7fyqa4qf7em4