生物谷報道：美國Emory大學的研究人員開發(fā)出一種新穎的抗腫瘤化合物，該化合物代表了一種截然不同的治療測量,，即靶向癌細胞最重要的一個攔截點（intercept point）。這項研究的結果刊登在2008年1月1日的Cancer Research雜志上,，并且成為雜志的封面故事,。這種化合物在2007年首次用于治療人類固體腫瘤。
攔截點策略背后的思路就是一次性堵死癌細胞中大量生長信號的傳遞,。領導該研究的Nonald L. Durden教授講癌細胞比作在開了太多燈的建筑物,。醫(yī)生通常只是通過關掉一個房間的燈來治療癌癥，而不是關掉電閘,。
Durden博士和同事靶向一類叫做PI-3激酶的蛋白酶,，這類酶是一個重要的攔截點，并且對身體中每個細胞都非常重要,。自然界制造出這些酶來控制生長,、分化和存活。
藥物研發(fā)的這種攔截點概念在2007年的《自然·臨床實踐神經學》雜志上進行了回顧,。研究人員發(fā)現(xiàn)了編碼PI-3激酶的基因,，并且發(fā)現(xiàn)這種基因在許多類型的腫瘤中發(fā)生了突變。另外,，一種對抗PI-3激酶的酶——PTEN磷酸酶在大部分人類前列腺癌,、腦癌、子宮內膜癌和乳腺癌中被失活,。
在Cancer Research上的文章中,，Durden博士和同事證實一種能針對所有PI-3激酶的化學抑制劑能夠終止小鼠中七種類型腫瘤的生長。
這種叫做SF1126的化合物能夠抵御前列腺癌,、乳腺癌,、腎癌、多發(fā)性骨髓瘤,、成神經細胞瘤,、神經膠質瘤和橫紋肌肉瘤。
2007年底,，美國亞利桑那州和印第安納州的醫(yī)生進行了SF1126的人類I期臨床試驗,。另外一項針對多發(fā)性骨髓瘤的I期臨床試驗將于2008年在Emory大學的Winship癌癥研究所等地展開。預計,，SF1126將于一年內開始兒科癌癥試驗,。
這種用RGD肽進行了標記的抑制劑能夠很容易融入身體并存留較長時間,。這種肽能使血管壁上的分子抓住這種化合物病將其送達腫瘤。
生物谷推薦原始出處：
Cancer Research 68, 206-215, January 1, 2008. doi: 10.1158/0008-5472.CAN-07-0669
Experimental Therapeutics, Molecular Targets, and Chemical Biology
A Vascular Targeted Pan Phosphoinositide 3-Kinase Inhibitor Prodrug, SF1126, with Antitumor and Antiangiogenic Activity
Joseph R. Garlich3, Pradip De1, Nandini Dey1, Jing Dong Su3, Xiaodong Peng3, Antoinette Miller3, Ravoori Murali4, Yiling Lu4, Gordon B. Mills4, Vikas Kundra4, H-K. Shu2, Qiong Peng1 and Donald L. Durden1
1 Section of Hematology/Oncology, Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta and 2 Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia; 3 Semafore Pharmaceuticals, Indianapolis, Indiana; and 4 Department of Experimental Therapeutics, M. D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Donald L. Durden, Aflac Cancer Center and Blood Disorders Service, Emory University School of Medicine, Atlanta, GA. Phone: 404-778-5118; E-mail: [email protected] .
PTEN and the pan phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1benzopyran-4-one (LY294002) exert significant control over tumor-induced angiogenesis and tumor growth in vivo. The LY294002 compound is not a viable drug candidate due to poor pharmacologic variables of insolubility and short half-life. Herein, we describe the development and antitumor activity of a novel RGDS-conjugated LY294002 prodrug, termed SF1126, which is designed to exhibit increased solubility and bind to specific integrins within the tumor compartment, resulting in enhanced delivery of the active compound to the tumor vasculature and tumor. SF1126 is water soluble, has favorable pharmacokinetics, and is well tolerated in murine systems. The capacity of SF1126 to inhibit U87MG and PC3 tumor growth was enhanced by the RGDS integrin (vβ3/5β1) binding component, exhibiting increased activity compared with a false RADS-targeted prodrug, SF1326. Antitumor activity of SF1126 was associated with the pharmacokinetic accumulation of SF1126 in tumor tissue and the pharmacodynamic knockdown of phosphorylated AKT in vivo. Furthermore, SF1126 seems to exhibit both antitumor and antiangiogenic activity. The results support SF1126 as a viable pan PI3K inhibitor for phase I clinical trials in cancer and provide support for a new paradigm, the application of pan PI3K inhibitory prodrugs for the treatment of cancer. [Cancer Res 2008;68(1):206–15]
分子診斷公司Source MDx日前宣布,，將于制藥巨頭輝瑞公司聯(lián)合研發(fā)與導致藥物抗性癌癥和炎癥相關的生物標志物,。
在多年的合作基礎上，這兩個公司將使用基因組合RNA轉錄分析方法在整個血液和循環(huán)細胞中鑒定炎癥和癌癥相關生物標志物,。
生物標志物的確定將為診斷技術的商業(yè)化帶了機遇,。Source MDx從輝瑞接收投資和技術專利費用于研究。Source MDx表示,，還將保留對所發(fā)現(xiàn)的診斷生物標志物德商業(yè)化權利,。
