摘要
目的评估表皮生长因子(EGFR)抑制剂AG1478与顺铂(CDDP)联合应用对人脑多形性胶质母细胞瘤(glioblastoma multiforme,GBM)裸小鼠脑原位移植瘤的疗效。方法人脑GBM裸小鼠脑内原位移植模型建立后第3天,将40只小鼠随机分为4组,每组10只,各组小鼠每次分别应用AG1478(25mg/kg)、CDDP(3mg/kg)、AG1478+CDDP(25mg/kg+3mg/kg)及PBS(0.1ml/只)。上述药物均腹腔注射,每2天1次,共4次,用药后观察各组荷瘤鼠生存期。重复上述实验步骤,肿瘤移植后14d处死各组小鼠取脑,HE染色后观察各组移植瘤形态及体积变化;EnVision法检测移植瘤中EGFRⅧ、磷酸化EGFRⅧ(P-EGFRⅧ)的表达及增殖活性变化;TUNEL法检测移植瘤细胞凋亡变化。结果与对照组[(19.4±0.6)d]比较,单用CDDP或AG1478荷瘤鼠生存期分别为(20.7±0.4)d和(20.8±0.6)d(P>0.05),而CDDP+AG1478组荷瘤鼠生存期为(33.6±0.9)d(P<0.05);CDDP+AG1478能明显减小移植瘤体积,降低增殖活性及促进肿瘤细胞凋亡,而单独用药对此效果不明显。结论AG1478与CDDP联合应用有协同的抗肿瘤疗效,这为EGFR抑制剂和常规化疗药物联合治疗恶性胶质瘤提供了实验依据。
Objective To evaluate the anti-tumor activity of an aqueous form of AG1478,and analyze the antitumor efficacy of combination of AG1478 with Cisplatin in the treatment for orthotopic xenografts from human gliobastoma multiforme tissues.Methods Orthotopic xenograft model of human gliobastoma multiforme with stable EGFRⅧ expression was established as described previously.On day 3 postinnoculation,40 mice were divided into 4 groups randomly with 10 in each group,then 4 groups of mice received i.p.injections of AG1478（25mg/kg）,Cisplatin（3mg/kg）,AG1478＋ Cisplatin（25mg/kg every time ＋3mg/kg）and PBS（0.1ml/20g）respectively every 2 days for 4 times,then their survival time was observed until the mice bearing xenografts died naturally.The experiment was repeated,in another 40 mice the same types of treatment were initiated on day 3.On day 14 after innnoculation,every group of mice were sacrified.Mice brains were removed from the cranial cavity,fixed with formalin,bisected coronally,and embedded in paraffin.Serial sections were stained with HE to observe tumor appearance and to measure the maximum or minimun diameter under light microscope to estimate tumor volume.The expression of EGFR,phosphorylated EGFR or Ki-67 in the xenografts were detected by immunochemical methods,and apoptosis were detected by TUNEL method.Results Compared with PBS group,the suvival were strikingly prolonged,and volume of xenografts were reduced by the combination of Cisplatin with AG1478.Meanwhile,the combined application could significantly decrease proliferative activity and increase apoptotic rate,but no effect could be seen for single drug.Conclusions The combination of AG1478 with Cisplatin can significantly increase the activities against tumor growth.This provides the rationale for its combination with both chemotherapy and other EGFR therapeutics.
出处
《北京医学》
CAS
2010年第5期361-365,共5页
Beijing Medical Journal
关键词
多形性胶质母细胞瘤
原位移植模型
顺铂
Glioblastoma multiforme（GBM） Orthotopic transplantation model Ciaplatin（CDDP）
