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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 efficacy of combined use of epidermal growth factor (EGFR) inhibitor AG1478 and cisplatin (CDDP) in the treatment of orthotopic transplanted brain tumor in nude mice with glioblastoma multiforme (GBM). Methods On the 3rd day after the in situ orthotopic transplantation of GBM in nude mice, 40 mice were randomly divided into 4 groups (10 rats in each group). AG1478 (25mg / kg) CDDP (3 mg / kg), AG1478 + CDDP (25 mg / kg + 3 mg / kg) and PBS (0.1 ml / only). The above drugs were injected intraperitoneally once every 2 days for a total of 4 times. After treatment, the survival of tumor-bearing mice in each group was observed. The above experimental procedure was repeated. The mice were sacrificed 14 days after the tumor transplantation, and the morphological changes and volume changes of the transplanted tumor were observed by HE staining. The expression of EGFRVIII and phosphorylated EGFRVIII (P-EGFRVIII) Activity changes; TUNEL assay of apoptotic tumor cells. Results Compared with the control group [(19.4 ± 0.6) d], the survival of tumor-bearing mice with CDDP or AG1478 alone was (20.7 ± 0.4) d and (20.8 ± 0.6) d, respectively (P> 0.05) The survival of tumor-bearing mice was (33.6 ± 0.9) d (P <0.05). CDDP + AG1478 could significantly reduce the volume of tumor xenografts, reduce the proliferative activity and promote the apoptosis of tumor cells. However, the effect of drug alone was not obvious. Conclusion The combination of AG1478 with CDDP has a synergistic antitumor effect, which provides an experimental basis for the combined treatment of glioblastoma with EGFR inhibitors and conventional chemotherapeutics.