The Bcl-2 Family Protein Inhibitor, Abt-737, Has Substantial Antimyeloma Activity And Shows Synergistic Effect With Dexamethasone And Melphalan

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 to ABT-737 with an EC50 of 0.2 and 0.5 mu mol/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 mu mol/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 mu mol/L ABT-737. As determined by colony assay, little or no detectable toxicity to patient hematologic progenitor cells was observed at 1 mu mol/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.