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

Authors' Affiliations: ¹ Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, and Department of Medicine, University of Toronto; ² Division of Cell and Molecular Biology, Toronto General Research Institute, Toronto General Hospital, University Health Network, and McLaughlin Centre for Molecular Medicine, Toronto, Canada; and ³ Division of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona

Requests for reprints: Xiao-Yan Wen, Princess Margaret Hospital, University Health Network, 620 University Avenue, Room 8-205, Toronto, Ontario, Canada M5G 2C1. Phone: 416-946-4435; Fax: 416-946-2087; E-mail: xywen{at}uhnres.utoronto.ca.

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 µmol/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 µmol/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 µmol/L ABT-737. As determined by colony assay, little or no detectable toxicity to patient hematologic progenitor cells was observed at 1 µmol/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.

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