全新长春氟宁衍生物体内外药效筛选  

In vitro and in vivo pharmacodynamic screening of novel vinflunine derivatives

作　　者：刘悦 雷新胜 宫爱申 肖亮 孙易 全海天[2] 徐永平[2] 唐卫东[2] 楼丽广[2] 邓炳初 

机构地区：[1]上海恒瑞医药有限公司,上海200245 [2]中国科学院上海生命科学院,上海药物研究所,上海201203

出　　处：《中国新药杂志》2008年第19期1659-1662,1683,共5页Chinese Journal of New Drugs

摘　　要：目的:对29个全新长春氟宁衍生物进行体内、外药效筛选,以期发现具有开发前景的抗肿瘤化合物。方法:体外筛选采用SRB法,移植人非小细胞肺癌A549裸小鼠模型作为体内药效模型。结果:通过体外IC50结果,结合化学结构,挑选出2个较有优势化合物:SHR115706和SHR115766,IC50分别为0.05和0.29μmol.L-1。SHR115706能够剂量依赖性的抑制裸鼠移植肿瘤的生长,抗癌疗效与长春氟宁相当;SHR115766亦可抑制肿瘤的生长,但剂量依赖性不明显。SHR115706(80 mg.kg-1),SHR115766(80 mg.kg-1)和长春氟宁(35 mg.kg-1,作为阳性对照)组肿瘤增殖速率分别为47.5%,57.6%和46.5%。SHR115706和SHR115766对裸鼠表现的毒性均明显低于长春氟宁。结论:SHR115706有望成为抗肿瘤新药。Objective：To screen a series of novel vinfunine derivatives in A549 cells in vitro and in human NSCLC A549 nude mice-transplanted tumors in vivo for discovering new candidate compounds with better curative effects and lower toxicities. Methods： Proliferation of A549 cells was measured by the method of SRB as the in vitro pharmacodynamic model. Human NSCLC A549 nude mice-transplanted tumor was used as the in vivo model. Results： The values of IC50 of the new derivatives were between 0.05 - 100 μmol·L^-1 in vitro. As a result, SHR115706 and SHR115766 were chosen as the candidate compounds because their IC50 was 0.05 μmol·L^-1 and 0.29μmol·L^-1, respectively. SHR115706 significantly inhibited tumors＇ growth（ P 〈 0.01 ） in a dose-dependent manner; while SHR115766 obviously inhibited the tumors＇ growth （P 〈 0.01 ） in a dose-independent manner. The proliferation rates of tumor cells after treatments with SHR115706 （80 mg·kg ^-1）, SHR115766 （80 mg·kg^-1） and vinfunine （35 mg·kg^-1 , the positive control） were 47.5% , 57.6% and 46.5% , respectively. SHR115706 and SHR115766 showed much smaller toxic effects than vinfunine in nude mice. Conclusion： SHR115706 is a superior and promising anticancer compound.

关 键 词：长春氟宁 抗肿瘤 体外筛选 

分 类 号：R979.1[医药卫生—药品] R965.1[医药卫生—药学]