Blood：ABT-737分子能增强儿童急性白血病的治疗效

    生物谷：研究儿童急性淋巴母细胞白血病（ALL）的药物治疗方法的科学家最近公布了1组新数据，他们首次证明，1种称为ABT-737的小分子能增加传统疗法的效果。  

    来自澳大利亚医学中心儿童肿瘤研究所的Richard  Lock博士是白血病生物学项目的负责人，他通过和洛杉矶儿童医院以及南加州大学合作取得了以上发现，结果发表在最近的权威刊物《血液》（Blood）上。  

    ALL是最常见的儿童肿瘤之1，在过去的数年间，初步治疗方面的进步已经帮助医生将这1疾病的治愈率提高到了大约80%，但是，对于那20%的发生了复发的病人而言，最终的结果很可能就是死亡。  

    Lock博士表示：“当我们对ALL病人进行的传统药物治疗方案中结合了ABT-737分子之后，小组发现ABT-737能提高这些药物对于白血病细胞的综合毒性，并且对于身体内的正常细胞产生的副作用被降到最低程度。”  

    对于那些长期治疗效果不佳的白血病人而言，对常规药物的抗药性是主要原因。而在此项研究中，小组测试了ABT-737和3种常用化疗药物结合后的效果：左旋天冬胺、长春新碱、地塞米松。  

    ABT-737是由Abbott实验室发明的，其主要作用是阻断bcl-2族蛋白质。这些蛋白质在ALL中得到表达，从而抑制对于破坏白血病细胞非常重要的机制。高浓度的bcl-2表达和多种肿瘤的化学抗药性有关。Lock博士说：“找到拥有新机制的全新药物对于提高ALL复发病人的康复率非常重要。” （教育部科技发展中心）

原始出处:

Blood First Edition Paper, prepublished online May 29, 2007

DOI 10.1182/blood-2007-03-080325

Submitted March 15, 2007
Accepted May 18, 2007

Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo

Min H. Kang*, Yun Hee Kang, Barbara Szymanska, Urszula Wilczynska-Kalak, Michael A. Sheard, Theresa Harned, Richard B. Lock, and C. Patrick Reynolds

Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles & USC, Los Angeles, CA, United States
Children's Cancer Instutute Australia for Medical Research, University of New South Wales, Sydney, Australia

* Corresponding author; email: mkang@chla.usc.edu .

Defects in apoptosis signaling contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), and overexpression of anti-apoptotic Bcl-2 (Bcl-2 and Bcl-XL) family proteins has been observed in ALL. ABT-737 is a small molecule BH3-mimetic that inhibits the anti-apoptotic bcl-2 family proteins. We evaluated the cytotoxicity of ABT-737 in combination with vincristine, dexamethasone, and L-asparaginase (VXL) in 7 ALL cell lines. Multi-log synergistic cytotoxicity was observed in all 7 cell lines with ABT-737 plus L-ASP or vincristine, and in 5 of 7 with ABT-737 plus dexamethasone or VXL. In leukemia cells, but not in normal lymphocytes, ABT-737 plus L-ASP induced greater mitochondrial depolarization (JC-1 staining), mitochondrial cytochrome c release, activation of Bax, Bid, and caspases (immunoblotting), and eventually apoptosis (annexin V staining), than did either drug alone. In mouse xenografts derived from ALL patients at diagnosis (ALL-7) or at relapse (ALL-19), event-free survival (EFS) was significantly enhanced with ABT-737 plus VXL relative to VXL or ABT-737 alone (P 0.02). Thus, ABT-737 synergistically enhanced VXL cytotoxicity in ALL cell lines via a mitochondrial death pathway and enhanced EFS in VXL-treated mice bearing ALL xenografts. Combining VXL with a BH3-mimetic warrants clinical investigation in ALL at relapse and potentially in chemotherapy-resistant ALL subgroups.

相关报道:

孕前感染疱疹可致儿童患急性白血病

儿童急性白血病与端粒酶活性有关

科学家辨认出与儿童急性淋巴性白血病复发有关的细胞

新基因准确预测儿童白血病治疗效果

Science：1种新的研究白血病的老鼠模型被建立

小儿急性白血病的护理

急性白血病预后