基于“NF-κB—抗凋亡”通路的扶正解毒法化疗增效减毒作用及其机理的研究

发布时间：2018-05-11 08:04

本文选题：非小细胞肺癌 + 扶正解毒法　；参考：《中国中医科学院》2015年博士论文

【摘要】：肺癌危害大,发病率、死亡率居高不下,其中占绝大多数的是非小细胞肺癌(NSCLC).化疗为目前主要的治疗方式之一,但因产生耐药性,疗效不佳,改善化疗耐药是提高疗效的有效途径。肿瘤耐药机制复杂,细胞凋亡受到抑制是其根本特性,癌细胞凋亡减少,细胞死亡率降低,引起化疗耐药。中医药结合化疗可以提高疗效,减轻毒副作用,为了验证临床效果和探索其作用机理,采用扶正解毒法(康艾注射液)配合化疗,设计临床观察和动物实验。目的：验证扶正解毒中药配合化疗时增效减毒的临床效果,以及探索其作用机理。方法：1.设计多中心前瞻随机对照临床试验,入组72例非小细胞肺癌化疗患者,分为单纯化疗组和中药(康艾)+化疗组,观察治疗前后瘤体变化和毒副反应。2.建立C57小鼠Lewis肺癌原位模型,给予扶正解毒中药及化疗干预;通过活体成像系统观察小鼠瘤体变化、体重增减和记录生存期。干预结束后取材,称量瘤重、脾重,流式CBA方法检测血清细胞因子,Western Blot方法检测NF-kB p65、Bcl-2、Bcl-X1蛋白表达,Tunel方法观察瘤细胞凋亡。结果：1.临床研究部分,中药(康艾)+化疗组能明显提高临床获益率(P0.05)；同时提高KPS评分(P0.05),在减轻化疗所致的恶心、呕吐、食欲下降等不良反应方面具有明显的作用(P0.05),可减轻化疗药物对骨髓的抑制作用和造成的肝肾功能损伤(P0.05)。2.实验研究部分,中药(康艾)+化疗组减少了小鼠体内炎性细胞因子水平(P0.05),降低了NF-kB及抗凋亡蛋白Bcl-2、Bcl-X1的表达,增加了小鼠肺癌细胞的凋亡(P0.05),疗程中期瘤体控制最小(P0.05),后期取材瘤重最小(P0.05),疗程中体重下降最少(P0.05),生存率最高(P0.05)。结论：1.扶正解毒法配合化疗,在临床中可以起到增效减毒的作用。2.动物实验中同样验证了扶正解毒法配合化疗的增效减毒作用；同时推断其可能的作用机理为,扶正解毒中药通过降低血清炎性细胞因子水平,减少NF-kB活化,从而阻断了“NF-kB—抗凋亡”通路,使肺癌细胞凋亡增加,提高了化疗疗效。
[Abstract]:Lung cancer is harmful, morbidity and mortality is high, in which the majority of non-small cell lung cancer is NSCLC. Chemotherapy is one of the main treatment methods at present, but because of drug resistance and poor curative effect, improving chemotherapeutic resistance is an effective way to improve the curative effect. The mechanism of drug resistance is complicated and the apoptosis is inhibited. The apoptosis of cancer cells decreases and the cell mortality decreases, which results in chemotherapeutic resistance. The combination of traditional Chinese medicine and chemotherapy can improve the curative effect and reduce the side effects. In order to verify the clinical effect and explore its mechanism, we designed clinical observation and animal experiment with Fuzheng detoxification method (Kangai injection) combined with chemotherapy. Objective: to verify the clinical effect of Fuzheng detoxification herbs combined with chemotherapy, and to explore its mechanism. Method 1: 1. A multicenter prospective randomized controlled clinical trial was designed. 72 patients with non-small cell lung cancer (NSCLC) were divided into simple chemotherapy group and traditional Chinese medicine (Kangai) chemotherapy group. The changes of tumor body and side effects were observed before and after treatment. The in situ model of Lewis lung cancer in C57 mice was established and treated with Fuzheng detoxification Chinese medicine and chemotherapeutic intervention. The changes of tumor body weight gain and loss and survival time were observed by in vivo imaging system. After the intervention, the tumor weight and spleen weight were measured, the serum cytokines were detected by flow cytometry, and the expression of Bcl-X1 protein in NF-kB p65 Bcl-2Bcl-X1 protein was detected by NF-kB p65 Bcl-2Bcl-X1. Apoptosis of tumor cells was observed by Tunel method. The result is 1: 1. In the clinical study, the Chinese medicine (Kangai) chemotherapy group could significantly increase the clinical benefit rate (P 0.05), and increase the KPS score (P 0.05) in reducing the nausea and vomiting caused by chemotherapy. The adverse reactions such as loss of appetite have obvious effect on P0.05, which can reduce the inhibitory effect of chemotherapeutic drugs on bone marrow and the damage of liver and kidney function caused by P0.05. 2. In the experimental study, the Chinese medicine (Kangai) chemotherapy group decreased the level of inflammatory cytokines (P0.05), and the expression of NF-kB and anti-apoptotic protein Bcl-X1 in mice. The apoptosis of lung cancer cells in mice was increased (P 0.05), the tumor body control was the lowest (P 0.05), the tumor weight was the lowest (P 0.05), the weight loss was the least (P 0.05), and the survival rate was the highest (P 0.05) during the course of treatment. Conclusion 1. Fuzheng detoxification method combined with chemotherapy, in clinical can play a synergistic and detoxification role. 2. In animal experiments, the synergistic and detoxifying effect of Fuzheng detoxification method combined with chemotherapy was also verified, and its possible mechanism was inferred that Fuzheng detoxification herbs could reduce the activation of NF-kB by reducing the level of serum inflammatory cytokines. Thus, the NF-kB-anti-apoptosis pathway was blocked, which increased the apoptosis of lung cancer cells and improved the chemotherapeutic effect.
【学位授予单位】：中国中医科学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R734.2

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