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目的目前食管癌放射治疗后5年生存率并不理想,可能原因是肿瘤细胞对放射线的抗拒从而降低了放射治疗的效果。厄洛替尼是表皮生长因子酪氨酸激酶抑制剂,对非小细胞肺癌和晚期胰腺癌均有明显的抑制作用,并能提高其放射治疗效果。由于食管癌组织中也存在表皮生长因子受体(epidermal growth factor receptor,EGFR)的高表达,提示厄洛替尼有可能成为治疗食管癌的一个靶向药物,并提高放射治疗的敏感性。本研究旨在探讨厄洛替尼联合X射线照射对人食管癌KYSE450细胞生长的影响。方法利用四氮唑盐(MTT)比色法分析厄洛替尼、X射线照射及两者联合对人食管癌KYSE450细胞的生长抑制作用,应用流式细胞仪分析细胞周期分布及细胞凋亡的变化。采用克隆形成实验检测厄洛替尼对食管癌细胞系放射敏感性的影响,用多靶单击模型拟合细胞存活曲线。结果厄洛替尼组、照射组和联合照射组对KYSE450细胞生长均有抑制作用,厄洛替尼对KYSE450细胞生长的抑制作用在5~150μg/mL呈剂量依赖性;且联合照射组对KYSE450细胞的生长抑制率为21.45%,明显高于厄洛替尼组的13.81%和照射组的16.84%,F=15.147,P<0.001。厄洛替尼与X射线都能增加肿瘤细胞G2期阻滞,且两者之间有交互作用,F=32.921,P<0.001。厄洛替尼与X射线都能促进肿瘤细胞凋亡,但两者在促进细胞凋亡方面尚未表现出交互作用,F=1.123,P=0.052。应用多靶单击模型求得,厄洛替尼联合照射组的平均致死剂量(D0)和准阈剂量(Dq)均较单纯照射组减小,放射增敏比(sensitization enhancement ratio,SER)为1.52;提示厄洛替尼对KYSE450细胞有放射增敏作用。结论厄洛替尼能有效抑制人食管癌KYSE450细胞的生长,与X射线照射联合后能够促进细胞凋亡,增强G2期阻滞效应,提高食管癌细胞放疗敏感性。
Objective The current 5-year survival rate of esophageal cancer after radiotherapy is not ideal, probably due to the radiation resistance of tumor cells and thus reduce the effect of radiation therapy. Erlotinib is an epidermal growth factor tyrosine kinase inhibitor, which has obvious inhibitory effect on non-small cell lung cancer and advanced pancreatic cancer, and can improve its radiotherapy effect. Due to the high expression of epidermal growth factor receptor (EGFR) in esophageal cancer tissues, it is suggested that erlotinib may be a target drug for esophageal cancer and improve the sensitivity of radiation therapy. The aim of this study was to investigate the effects of erlotinib combined with X-ray irradiation on the growth of human esophageal carcinoma KYSE450 cells. Methods MTT assay was used to analyze the effects of erlotinib, X-ray irradiation and their combination on the growth of human esophageal carcinoma KYSE450 cells. The cell cycle distribution and apoptosis were analyzed by flow cytometry Variety. The effect of erlotinib on radiosensitivity of esophageal cancer cell lines was tested by clonogenic assay. Cell survival curves were fitted by multi-target click model. Results The growth of KYSE450 cells was inhibited in the erlotinib group, the irradiated group and the combined irradiation group. The inhibitory effect of erlotinib on the growth of KYSE450 cells was dose-dependent at a dose of 5-150 μg / mL. The combination of KYSE450 The growth inhibition rate of cells was 21.45%, which was significantly higher than 13.81% of the erlotinib group and 16.84% of the irradiated group, F = 15.147, P <0.001. Both erlotinib and X-ray can increase the G2 arrest of tumor cells, and there is interaction between the two, F = 32.921, P <0.001. Erlotinib and X-rays can promote tumor cell apoptosis, but both have not shown any interaction in promoting apoptosis, F = 1.123, P = 0.052. The results of multi-target click model showed that the average lethal dose (D0) and quasi-threshold dose (Dq) of erlotinib combined irradiation group decreased compared with those of pure irradiation group, and the sensitization enhancement ratio (SER) 1.52; suggesting that erlotinib has a radiosensitizing effect on KYSE450 cells. Conclusion Erlotinib can effectively inhibit the growth of human esophageal carcinoma KYSE450 cells. Combined with X-ray irradiation, erlotinib can promote cell apoptosis, enhance the arrest effect of G2 phase and enhance the radiosensitivity of esophageal cancer cells.