生物谷：研究兒童急性淋巴母細胞白血?。ˋLL）的藥物治療方法的科學家最近公布了一組新數據，他們首次證明,，一種稱為ABT-737的小分子能增加傳統療法的效果,。
來自澳大利亞醫(yī)學中心兒童腫瘤研究所的Richard Lock博士是白血病生物學項目的負責人，他通過和洛杉磯兒童醫(yī)院以及南加州大學合作取得了以上發(fā)現，結果發(fā)表在最近的權威刊物《血液》（Blood）上,。
ALL是最常見的兒童腫瘤之一,，在過去的數年間，初步治療方面的進步已經幫助醫(yī)生將這一疾病的治愈率提高到了大約80%,，但是,，對于那20%的發(fā)生了復發(fā)的病人而言，最終的結果很可能就是死亡,。
Lock博士表示：“當我們對ALL病人進行的傳統藥物治療方案中結合了ABT-737分子之后,，小組發(fā)現ABT-737能提高這些藥物對于白血病細胞的綜合毒性，并且對于身體內的正常細胞產生的副作用被降到最低程度,。”
對于那些長期治療效果不佳的白血病人而言,，對常規(guī)藥物的抗藥性是主要原因。而在此項研究中,，小組測試了ABT-737和3種常用化療藥物結合后的效果：左旋天冬胺,、長春新堿、地塞米松,。
ABT-737是由Abbott實驗室發(fā)明的,，其主要作用是阻斷Bcl-2族蛋白質。這些蛋白質在ALL中得到表達,，從而抑制對于破壞白血病細胞非常重要的機制,。高濃度的Bcl-2表達和多種腫瘤的化學抗藥性有關。Lock博士說：“找到擁有新機制的全新藥物對于提高ALL復發(fā)病人的康復率非常重要,。” （教育部科技發(fā)展中心）
原文鏈接：http://www.physorg.com/news103812681.html
原始出處:
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: [email protected] .
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.
