Trudel Suzanne, Stewart A Keith, Li Zhihua, Shu Yanjun, Liang Sheng-Ben, Trieu Young, Reece Donna, Paterson Josh, Wang Dingyan, Wen Xiao-Yan
Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, 620 University Avenue, Toronto, Ontario, Canada.
Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):621-9. doi: 10.1158/1078-0432.CCR-06-1526.
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.
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.
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.
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.
本研究旨在探讨新型Bcl-2家族抑制剂ABT-737在多发性骨髓瘤临床前治疗中的抗骨髓瘤活性。
在培养的骨髓瘤细胞系和患者骨髓瘤样本以及异种移植小鼠骨髓瘤模型中评估ABT-737的抗骨髓瘤活性。还研究了ABT-737与其他常用骨髓瘤药物的联合治疗。
MY5和JJN3细胞系对ABT-737表现出最高敏感性，其半数有效浓度（EC50）分别为0.2和0.5微摩尔/升，细胞凋亡增加，活化的半胱天冬酶-3水平升高。我们确定了两组对该药物敏感或耐药的骨髓瘤患者样本。15例患者骨髓样本中有4例（27%）对0.25和0.5微摩尔/升剂量的ABT-737高度敏感，药物治疗3天后，由于细胞凋亡，骨髓瘤细胞减少了80%至90%。ABT-737与地塞米松或美法仑联合使用时，在诱导骨髓瘤细胞死亡方面显示出协同作用。此外，地塞米松耐药的MM1（Dex）R骨髓瘤细胞系对0.2微摩尔/升ABT-737高度敏感。通过集落测定法确定，在1微摩尔/升ABT-737时，对患者血液祖细胞几乎没有或没有可检测到的毒性。在异种移植MY5小鼠模型中，ABT-737剂量依赖性地抑制肿瘤生长。
这些研究表明，ABT-737作为单一药物或与地塞米松或美法仑联合使用具有显著的抗骨髓瘤活性，并为未来的临床试验提供了理论依据。
