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目的观察7个FCN系列表皮生长因子受体(EGFR)酪氨酸激酶抑制剂对H1975细胞体内外抗肿瘤作用。方法采用非小细胞肺癌(NSCLC)H1975细胞(T790M突变)和人表皮鳞癌A431细胞(WT-EGFR)体外增殖抑制试验对7个FCN系列化合物进行筛选,得到抗肿瘤活性强且选择性更好的化合物。通过细胞划痕实验、流式细胞术分别测定化合物对细胞迁移能力、细胞周期和凋亡的影响,通过H1975细胞裸鼠移植瘤实验明确化合物在体内对肿瘤生长的影响。结果 H1975细胞增殖实验筛选出高活性化合物FCN12、FCN14和FCN15,半数抑制浓度(IC50)分别为(103.33±12.10)、(115.17±7.69)和(128.63±32.72)nmol·L~(-1);经A431细胞增殖实验筛选出FCN12、FCN14,两者的体外抗细胞增殖抑制活性与对照药AZD9291相当(IC50>2μmol·L~(-1)),并可将H1975细胞阻滞于G1期;与对照药相比,FCN12、FCN14可明显增加细胞凋亡率(P<0.01)和抑制细胞的迁移(P<0.05),且呈浓度依赖性;体内移植瘤实验结果显示FCN12、FCN14可以明显抑制肿瘤的生长并缩小肿瘤体积(P<0.01)。结论新型EGFR抑制剂FCN12、FCN14对EGFR耐药型NSCLC具有显著的体内外抗肿瘤活性。
Objective To observe the antitumor effects of seven FCN series epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors on H1975 cells in vitro and in vivo. Methods Seven FCN series of compounds were screened by in vitro proliferation inhibition of H1975 cells (T790M mutation) and human epidermoid squamous cell carcinoma A431 cells (WT-EGFR) in non-small cell lung cancer (NSCLC), resulting in better antitumor activity and selectivity compound of. The effects of the compounds on cell migration, cell cycle and apoptosis were determined by cell scratch assay and flow cytometry respectively. The effects of the compounds on tumor growth in vivo were confirmed by H1975 cell xenografts in nude mice. Results The proliferation inhibitory activity of H1975 cells was high (103.33 ± 12.10), (115.17 ± 7.69) and (128.63 ± 32.72) nmol·L -1, respectively. The high activity compounds FCN12, FCN14 and FCN15 were screened out. FCN12 and FCN14 were screened by A431 cell proliferation assay. The in vitro anti-cell proliferation inhibitory activity was comparable to that of AZD9291 (IC50> 2μmol·L -1), and inhibited the arrest of H1975 cells in G1 phase. FCN12 and FCN14 could significantly increase the apoptosis rate (P <0.01) and inhibit the migration of cells (P <0.05) in a dose-dependent manner. The results of in vivo transplantation tumor showed that FCN12 and FCN14 could significantly inhibit tumor Growth and tumor volume (P <0.01). Conclusion The new EGFR inhibitors FCN12 and FCN14 have significant antitumor activity against EGFR-resistant NSCLC in vitro and in vivo.