近日，根據(jù)研究美國(guó)俄亥俄州立大學(xué)綜合癌癥中心的研究人員完成額一項(xiàng)研究證實(shí)：一種穿梭于細(xì)胞核內(nèi)的蛋白質(zhì)分子可能是治療急性白血病患者新的作用靶標(biāo),。
抑制這一蛋白質(zhì)家族的藥物叫KPT-SINEs,，能靶向調(diào)控運(yùn)輸?shù)鞍?mdash;—CRM1。在急性髓細(xì)胞性白血病（AML）細(xì)胞和動(dòng)物模型研究中，研究人員發(fā)現(xiàn)這些藥物能抑制白血病細(xì)胞增殖，阻斷細(xì)胞分裂并誘導(dǎo)細(xì)胞死亡和分化,。
在AML動(dòng)物模型中，與對(duì)照組相比,，KPT-SINEs能延長(zhǎng)動(dòng)物46％的存活時(shí)間,。
KPT-SINEs對(duì)有NPM1腫瘤抑制基因突變的白血病細(xì)胞特別有效，這類突變白血病患者占所有成人白血病患者的三分之一左右,。
這項(xiàng)研究結(jié)果發(fā)表在Blood雜志上,。
醫(yī)學(xué)助理教授Ramiro Garzon稱：我們的研究表明這些藥物可能是一個(gè)有效的治療藥物，特別是對(duì)AML NPM1突變患者來(lái)說(shuō),。
研究人員我們希望盡快將這些藥物啟動(dòng)臨床試驗(yàn),，并進(jìn)一步研究其與目前其他化療藥物結(jié)合使用情況。（生物谷：Bioon.com）
doi:10.1182/blood-2012-04-423160
PMC:
PMID:
Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia
Parvathi Ranganathan, Xueyan Yu, Caroline Na, Ramasamy Santhanam, Sharon Shacham, et al.
CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors [e.g. p53 and nucleophosmin] whose function is altered in cancer due to increased expression and overactive transport. Blocking CRM1 mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here, we investigated the anti-leukemic activity of KPT-SINE (KPT-185 and -276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent anti-proliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5 fold increase), cell-cycle arrest and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild type cell lines was observed. Finally, using the FLT3-ITD positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P<0.01). In summary, KPT-SINEs are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.
