奥希替尼联合贝伐珠单抗治疗伴EGFR T790M突变肺腺癌的疗效与机制研究

发布时间：2018-02-24 18:31

本文关键词： 非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂抗血管生成治疗肿瘤微环境　出处：《中国肿瘤临床》2017年15期 　论文类型：期刊论文

【摘要】：目的:通过移植瘤动物实验探讨奥希替尼联合抗VEGF单克隆抗体靶向药物贝伐珠单抗的疗效及作用机制,为进一步临床试验提供理论依据。方法:构建EGFR T790M突变的H1975人肺腺癌细胞移植瘤动物模型。实验分组:低剂量奥希替尼组、高剂量奥希替尼组、低剂量奥希替尼联合贝伐珠单抗组、高剂量奥希替尼联合贝伐珠单抗组。每组各5只小鼠,给药方法:奥希替尼2.5 mg/kg/d或5 mg/kg/d,采用每天灌胃处理;贝伐珠单抗5 mg/kg,每周2次腹腔注射。接种后和给药期间绘制肿瘤生长曲线,给药2周后处死裸鼠,活检整个肿瘤。免疫组织化学SP法检测肿瘤HIF-1α、VEGF和微血管密度(microvessel density,MVD)。应用Western blot法检测EGFR及其下游AKT和ERK信号通路蛋白的表达。结果:给药2周后,高剂量奥希替尼单药组较低剂量奥希替尼单药组肿瘤体积明显缩小,HIF-1α、VEGF表达率和MVD显著降低(P0.05),p-EGFR、p-AKT和p-ERK表达减少(P0.05)。低剂量奥希替尼联合贝伐珠单抗组肿瘤体积明显小于低剂量奥希替尼单药组(P0.05),上述因子均明显降低(P0.05)。低剂量奥希替尼联合组与高剂量奥希替尼单药组比较,肿瘤体积差异无统计学意义(P=0.178),p-EGFR、p-AKT、p-ERK表达差异无统计学意义(P0.05)。高剂量奥希替尼联合组与高剂量奥希替尼单药组体积差异无统计学意义(P=0.642)。两个联合组之间,体积差异均无统计学意义(P=0.072),上述因子表达差异均无统计学意义(P0.05)。结论:贝伐珠单抗能够显著增加奥希替尼对伴EGFR T790M突变的肺腺癌移植瘤的杀伤能力。贝伐珠单抗与奥希替尼协同作用是通过降低肿瘤中VEGF表达,改善肿瘤微环境,增强抑制EGFR下游信号通路激活而实现的。
[Abstract]:Objective: to investigate the therapeutic effect and mechanism of omitinib combined with monoclonal antibody against VEGF targeting bevacizumab. Methods: the animal model of H1975 human lung adenocarcinoma cell transplantation tumor with EGFR T790M mutation was established. Low dose Ochitinib combined with bevacizumab group and high dose Ochitinib combined bevacizumab group with 5 mice in each group were treated by oral administration of oxitinib 2.5 mg/kg/d or 5 mg / kg / d. Bevacizumab, 5 mg / kg, was injected intraperitoneally twice a week. The tumor growth curve was drawn after inoculation and administration, and the nude mice were killed 2 weeks after administration. HIF-1 伪 -VEGF and microvessel density were detected by immunohistochemical SP method. The expression of EGFR and its downstream AKT and ERK signaling pathway proteins were detected by Western blot method. Results: two weeks after administration, the expression of EGFR and its downstream AKT and ERK signaling pathway proteins were detected. The tumor volume of high dose omitinib group was significantly smaller than that of low dose oxitinib group, and the expression rate of HIF-1 伪 -VEGF and MVD were significantly lower than that of low dose omitinib group. The tumor volume of low dose Ochitinib combined with bevacizumab group was significantly smaller than that of low dose oxitinib combined with bevacizumab group. In the low dose Ochitinib group, the above factors were all significantly lower than those in the high dose Ochitinib group, and the low dose Ochitinib combined group was significantly lower than the High dose Ochitinib group, and there was no significant difference between the two groups. There was no significant difference in tumor volume between the two groups. There was no significant difference in the expression of p-EGFRN p-AKTnp-ERK between the two groups. There was no significant difference in volume between the high dose Ochitinib combined group and the high dose Ochitinib single drug group (P < 0. 642), and there was no significant difference between the two groups, and there was no significant difference in the volume between the two groups, and there was no significant difference between the two groups. There was no significant difference in volume, but there was no significant difference in the expression of these factors. Conclusion: bevacizumab can significantly increase the cytotoxicity of Ochitinib to transplanted tumor of lung adenocarcinoma with EGFR T790M mutation. The synergistic effect with Ochitinib is by reducing the expression of VEGF in the tumor. Improved tumor microenvironment and enhanced inhibition of activation of downstream signal pathway of EGFR.
【作者单位】：中国医科大学附属盛京医院第一肿瘤科;
【基金】：辽宁省高等学校杰出青年学者成长计划项目(编号:LJQ2014082)资助~~
【分类号】：R734.2

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