Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB, Canada.
Leuk Res. 2011 Dec;35(12):1649-57. doi: 10.1016/j.leukres.2011.06.035. Epub 2011 Jul 27.
Although recent decades have seen a significant improvement in the treatment outcome of leukemia in the pediatric population, those who are treated for relapsed disease still face significant morbidity and mortality. However, current salvage regimens are often assembled with agents that have similar mode of activity as the chemotherapeutics used in the initial treatment. Hence, novel therapeutic agents that are capable of distinct and diverse mechanisms of activity in, now resistant, leukemia cells are of great interest. We have investigated the opioid agonist methadone for its anti-leukemic activity, initially reported in studies with cell lines derived from adult patients. Our findings show that, compared to normal cells, methadone has enhanced cytotoxicity against specimens and cell lines established from refractory childhood leukemia. In addition, methadone's activity synergized with that of the anti-Bcl-2 agent ABT-737 and was characterized by the induction of distinct changes in tumor cell mitochondria. Data presented also identify biological correlates and a potential mechanism for methadone activity by its effects on Mcl-1 and other members of the apoptosis cascade. We provide mechanistic data for the therapeutic potential of a family of agents that is largely unexplored for anti-leukemic activity.
尽管近几十年来儿科人群白血病的治疗结果有了显著改善，但那些接受复发疾病治疗的患者仍然面临着显著的发病率和死亡率。然而，目前的挽救方案通常是用与初始治疗中使用的化疗药物具有相似作用模式的药物组合而成。因此，对于现在耐药的白血病细胞具有独特而多样作用机制的新型治疗药物具有极大的研究价值。我们已经研究了阿片类激动剂美沙酮的抗白血病活性，最初是在对源自成年患者的细胞系的研究中报道的。我们的研究结果表明，与正常细胞相比，美沙酮对来自难治性儿童白血病的标本和细胞系具有更强的细胞毒性。此外，美沙酮的活性与抗 Bcl-2 药物 ABT-737 协同作用，并表现为诱导肿瘤细胞线粒体的明显变化。所呈现的数据还通过其对 Mcl-1 和凋亡级联的其他成员的影响，确定了美沙酮活性的生物学相关性和潜在机制。我们提供了一组在抗白血病活性方面基本上尚未得到探索的药物的治疗潜力的机制数据。
