生物谷报道：美国Emory大学的研究人员开发出一种新颖的抗肿瘤化合物，该化合物代表了一种截然不同的治疗测量，即靶向癌细胞最重要的一个拦截点（intercept point）。这项研究的结果刊登在2008年1月1日的Cancer Research杂志上，并且成为杂志的封面故事。这种化合物在2007年首次用于治疗人类固体肿瘤。
拦截点策略背后的思路就是一次性堵死癌细胞中大量生长信号的传递。领导该研究的Nonald L. Durden教授讲癌细胞比作在开了太多灯的建筑物。医生通常只是通过关掉一个房间的灯来治疗癌症，而不是关掉电闸。
Durden博士和同事靶向一类叫做PI-3激酶的蛋白酶，这类酶是一个重要的拦截点，并且对身体中每个细胞都非常重要。自然界制造出这些酶来控制生长、分化和存活。
药物研发的这种拦截点概念在2007年的《自然·临床实践神经学》杂志上进行了回顾。研究人员发现了编码PI-3激酶的基因，并且发现这种基因在许多类型的肿瘤中发生了突变。另外，一种对抗PI-3激酶的酶——PTEN磷酸酶在大部分人类前列腺癌、脑癌、子宫内膜癌和乳腺癌中被失活。
在Cancer Research上的文章中，Durden博士和同事证实一种能针对所有PI-3激酶的化学抑制剂能够终止小鼠中七种类型肿瘤的生长。
这种叫做SF1126的化合物能够抵御前列腺癌、乳腺癌、肾癌、多发性骨髓瘤、成神经细胞瘤、神经胶质瘤和横纹肌肉瘤。
2007年底，美国亚利桑那州和印第安纳州的医生进行了SF1126的人类I期临床试验。另外一项针对多发性骨髓瘤的I期临床试验将于2008年在Emory大学的Winship癌症研究所等地展开。预计，SF1126将于一年内开始儿科癌症试验。
这种用RGD肽进行了标记的抑制剂能够很容易融入身体并存留较长时间。这种肽能使血管壁上的分子抓住这种化合物病将其送达肿瘤。
生物谷推荐原始出处：
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: dldurde@emory.edu .
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]
分子诊断公司Source MDx日前宣布，将于制药巨头辉瑞公司联合研发与导致药物抗性癌症和炎症相关的生物标志物。
在多年的合作基础上，这两个公司将使用基因组合RNA转录分析方法在整个血液和循环细胞中鉴定炎症和癌症相关生物标志物。
生物标志物的确定将为诊断技术的商业化带了机遇。Source MDx从辉瑞接收投资和技术专利费用于研究。Source MDx表示，还将保留对所发现的诊断生物标志物德商业化权利。
