Cao Wei-Guo, Ma Tao, Li Jian-Fang, Li Hao, Ji Yu-Bao, Chen Xue-Hua, Liu Bing-Ya, Jin Ye-Ning
Department of Oncology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, PR China.
Ai Zheng. 2007 Dec;26(12):1330-5.
BACKGROUND & OBJECTIVE: Epidermal growth factor receptor (EGFR) is expressed in most human epithelial cancers and is involved in the development of cancer cell resistance to irradiation. We used gefitinib, a selective EGFR tyrosine kinase inhibitor (EGFR-TKI), to investigate its effects and mechanisms in enhancing the radiosensitivity of human gastric cancer cell lines in vitro.
The expression of EGFR protein in 7 human gastric cell lines (MKN45, SGC7901, SNU-1, N87, AGS, SNU-16, and KATO-III) was determined by Western blot, in which 2 cell lines with high expression of EGFR were selected for additional test. The inhibitory effect of gefitinib on cell proliferation was measured by MTT assay. Cell survival was determined by clonogenic assay, and then the radiosensitivity parameters were calculated. The effects of gefitinib in combination with radiation on cell apoptosis and cell cycle distribution were analyzed by flow cytometry.
Of the 7 gastric cancer cell lines, the expression of EGFR in MKN45 and SGC7901 cells were the highest. The 50% inhibition concentrations (IC(50)) of gefitinib were 0.4 mmol/L for MKN45 cells and 0.8 mmol/L for SGC7901 cells. Cell survival was significantly decreased with the elevation of gefitinib concentration or radiation dose (P<0.05). When treated with 0.1x and 0.2 x IC(50) of gefitinib, the radiosensitization enhancement ratios (SER) of MKN45 cells were 1.102 and 1.154, and those of SGC7901 cells were 1.092 and 1.176, respectively. Either gefitinib or radiation induced cell apoptosis, reduced the percentage of cells at S phase and increased the percentage of cells at G(2)/M phase (P<0.01).
Gefitinib followed by radiation could increase the radiosensitivity of MKN45 and SGC7901 cells with high expression of EGFR and inhibit cell proliferation, induce apoptosis, and alter cell phase distribution. Gefitinib could be a radiation sensitizer for gastric tumors with high expression of EGFR.
表皮生长因子受体（EGFR）在大多数人类上皮癌中表达，并参与癌细胞对辐射的抗性发展。我们使用吉非替尼，一种选择性EGFR酪氨酸激酶抑制剂（EGFR-TKI），来研究其在体外增强人胃癌细胞系放射敏感性的作用及机制。
通过蛋白质免疫印迹法测定7种人胃癌细胞系（MKN45、SGC7901、SNU-1、N87、AGS、SNU-16和KATO-III）中EGFR蛋白的表达，从中选择2种EGFR高表达的细胞系进行进一步检测。采用MTT法检测吉非替尼对细胞增殖的抑制作用。通过克隆形成试验测定细胞存活率，然后计算放射敏感性参数。采用流式细胞术分析吉非替尼联合辐射对细胞凋亡和细胞周期分布的影响。
在7种胃癌细胞系中，MKN45和SGC7901细胞中EGFR的表达最高。吉非替尼对MKN45细胞的半数抑制浓度（IC(50)）为0.4 mmol/L，对SGC7901细胞为0.8 mmol/L。随着吉非替尼浓度或辐射剂量的升高，细胞存活率显著降低（P<0.05）。当用0.1x和0.2x IC(50)的吉非替尼处理时，MKN45细胞的放射增敏增强率（SER）分别为1.102和1.154，SGC7901细胞的分别为1.092和1.176。吉非替尼或辐射均可诱导细胞凋亡，降低S期细胞百分比，增加G(2)/M期细胞百分比（P<0.01）。
先使用吉非替尼再进行辐射可增加EGFR高表达的MKN45和SGC7901细胞的放射敏感性，抑制细胞增殖，诱导凋亡，并改变细胞周期分布。吉非替尼可能是EGFR高表达胃肿瘤的放射增敏剂。
