EGFR单克隆抗体在头颈鳞癌中应用的meta分析及药物增敏策略研究

发布时间：2018-11-11 10:11

【摘要】：目的：通过meta分析方法,研究表皮生长因子单克隆抗体(EGFR-Mabs)治疗头颈鳞癌的有效性和安全性。在此基础上,研究双氢青蒿素(DHA)、盐酸二甲双胍(metformin)和AG490对Fadu细胞系西妥昔(Cetuximab)台疗的增敏作用及机制。方法：检索中国生物医学文献数据库(CBM)、PUBMED、EMBASE和CENTRAL数据库。分析指标为总体反应率(over response rate,ORR)、无进展生存情况(progression-free survival,PFS)和总体生存情况(overall survival,OS)。不良反应主要观察3-4级严重不良反应。结果评价使用相对危险度(Relative Risk,RR)或风险比(Hazard Rate,HR)及其相应95%可信区间(95%CI)表示。MTT等效线图解法研究Fadu细胞系中DHA、metformin和AG490分别与Cetuximab联用产生的作用；Western blot技术检测不同药物处理下Fadu细胞中p-STAT3、T-STAT3、p-MAPK、 Bcl-xl、Mcl-1、Cyclin D1、VEGF蛋白的表达情况。采用流式细胞术检测不同药物处理下Fadu细胞的凋亡情况。结果：(1)对于复发/转移头颈鳞癌患者(ORR:RR:1.61,95% CI:1.34-1.92,P0.001; PFS:HR:0.68,95%CI:0.61-0.76, P0.001; OS:HR:0.84,95%CI:0.75-0.95, P=0.004)。(2)对于局部晚期头颈鳞癌患者(ORR 1.21,0.97-1.49; PFS 0.87,0.75-1.01; OS 0.82,0.71-0.95)。(3)以Cetuximab为例,晚期头颈鳞癌患者,2年无进展生存率和总体生存率在加用Cetuximab组与未使用Cetuximab组中无明显差别(PFS:RR=1.02, 95%CI 0.92-1.12; P= 0.76; OS:RR=1.06,95%CI 1.00-1.13, P= 0.06);复发和转移头颈鳞癌患者,使用Cetuximab组总体生存时间、无进展生存时间和总体反应率均优于未使用Cetuximab组(OS:MD=2.41,95%CI 0.96-3.86,P=0.001;PFS:MD=2.06, 95%CI 1.34-2.77,P0.00001; ORR:OR=2.38,95% CI 1.60-3.54,P0.00001)。而1年生存率未显示明显提高(OR=1.39,95% CI 0.98-1.97, P=0.07)。(4)EGFR-Mabs治疗组更多出现以皮肤反应为代表严重不良反应事件。(5)Fadu细胞系中使用MTT等效线图解法研究DHA、metformin和AG490与Cetuximab联用,分别产生拮抗、相加和协同作用；Western blot技术检测Fadu细胞中p-STAT3、T-STAT3、p-MAPK、 Bcl-x1、Mcl-1、Cyclin D1、VEGF蛋白的表达情况,metformin及AG490与Cetuximab联用明显减少p-STAT3及其下游因子Bcl-xl、Mcl-1、Cyclin D1、VEGF蛋白的表达。流式细胞仪检测显示Fadu细胞中,metformin及AG490与Cetuximab联用增加凋亡。结论：EGFR-Mabs治疗头颈鳞癌患者总体有效,但由于治疗抵抗存在,其临床效果并不满意。以皮肤反应为代表的严重3-4级不良反应在EGFR-Mabs治疗组多见,差异具有统计学意义。DHA与Cetuximab联用呈现拮抗效应,机制有待进一步研究。metformin和AG490与Cetuximab在一定条件下联用具有增敏效果,可能与其联合阻滞相关信号通路有关。
[Abstract]:Objective: to study the efficacy and safety of epidermal growth factor monoclonal antibody (EGFR-Mabs) in the treatment of head and neck squamous cell carcinoma by meta analysis. On this basis, the sensitizing effect and mechanism of dihydroartemisinin (DHA), hydrochloride metformin (metformin) and AG490 on Fadu cell line (Cetuximab) were studied. Methods: Chinese biomedical literature database (CBM), PUBMED,EMBASE and CENTRAL were searched. Total response rate (over response rate,ORR), progressive survival (progression-free survival,PFS) and total survival (overall survival,OS) were analyzed. Adverse reactions were observed mainly in grade 3-4 severe adverse reactions. Results the evaluation was expressed by relative risk (Relative Risk,RR) or risk ratio (Hazard Rate,HR) and its corresponding 95% confidence interval (95%CI). The effect of DHA,metformin and AG490 combined with Cetuximab in Fadu cell line was studied by MTT equivalent graph method. Western blot technique was used to detect the expression of p-STAT _ (3) T _ (STAT _ (3) -MAPK and Bcl-xl,Mcl-1,Cyclin D _ (1) protein in Fadu cells treated with different drugs. Flow cytometry was used to detect the apoptosis of Fadu cells treated with different drugs. Results: (1) in patients with recurrent / metastatic head and neck squamous cell carcinoma (ORR:RR:1.61,95% CI:1.34-1.92,P0.001; PFS:HR:0.68,95%CI:0.61-0.76, P 0.001); OS:HR:0.84,95%CI:0.75-0.95, P0. 004). (2 was used to treat locally advanced head and neck squamous cell carcinoma patients (ORR 1.21, 0.97-1.49, PFS 0.87, 0.75-1.01respectively). OS 0.82n 0.71-0.95). (3) in Cetuximab patients with advanced head and neck squamous cell carcinoma, there was no significant difference in 2-year progression-free survival rate and overall survival rate between Cetuximab group and non-Cetuximab group (PFS:RR=1.02,). 95%CI 0.92-1.12; P = 0.76; OS:RR=1.06,95%CI 1.00-1.13, P = 0.06); In patients with recurrent and metastatic head and neck squamous cell carcinoma, the overall survival time, progression free survival time and overall response rate in Cetuximab group were significantly higher than those in Cetuximab group (OS:MD=2.41,95%CI 0.96-3.86 PnP 0.001). PFS:MD=2.06, 95%CI 1.34-2.77, P0.00001; ORR:OR=2.38,95% CI 1.60-3.54, P0.00001). The 1-year survival rate did not increase significantly (OR=1.39,95% CI 0.98-1.97). (5) in the Fadu cell line, the combination of DHA,metformin, AG490 and Cetuximab was studied by using MTT equivalent graph method, and antagonistic effects were produced, respectively, in the EGFR-Mabs treatment group, which was characterized by skin reaction as the representative of severe adverse reaction. (5) in the Fadu cell line, the combination of DHA,metformin and AG490 with Cetuximab was studied by MTT equivalent graph method. Addition and synergy; Western blot technique was used to detect the expression of p-STAT3T-STAT3pMAPK and Bcl-x1,Mcl-1,Cyclin D1 protein in Fadu cells. The combination of metformin and AG490 with Cetuximab significantly reduced p-STAT3 and its downstream factor Bcl-xl,Mcl-1,Cyclin D1. Expression of VEGF protein. Flow cytometry showed that metformin, AG490 and Cetuximab increased apoptosis in Fadu cells. Conclusion: EGFR-Mabs is effective in the treatment of head and neck squamous cell carcinoma, but its clinical effect is not satisfactory due to the existence of treatment resistance. Severe grade 3-4 adverse reactions, represented by skin reactions, were more common in the EGFR-Mabs treatment group, and the difference was statistically significant. The combination of DHA and Cetuximab showed antagonistic effect. The mechanism needs further study. The combination of metformin and AG490 with Cetuximab can enhance the sensitivity under certain conditions, which may be related to their combined blocking of related signaling pathways.
【学位授予单位】：中国人民解放军医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R739.91

【相似文献】