Blood：ABT-737分子能增强儿童急性白血病的治疗效果

irisln

Blood：ABT-737分子能增强儿童急性白血病的治疗效果 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一组新数据，他们首次证明，一种称为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RichardLock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一，在过去的数年间，初步治疗方

  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一组新数据，他们首次证明，一种称为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一，在过去的数年间，初步治疗方面的进步已经帮助医生将这一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）

  原文链接：http://www.physorg.com/news103812681.html  

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.