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目的:研究新型小分子酪氨酸激酶抑制剂NXGH和NXGF对不同EGFR表达水平及突变状态肺癌细胞的敏感性,为构建EGFR分子分型成像探针提供参考依据。方法:构建基于NXG结构的新型小分子酪氨酸激酶抑制剂NXGH和NXGF,选择4种不同EGFR表达水平及突变状态肺癌细胞:PC9(EGFR 19外显子缺失突变)、H1975(EGFR L858R突变合并T790M二次突变)、H358(EGFR野生型表达)及H520(EGFR阴性表达),应用MTT方法分析梯度浓度NXGH及NXGF 48 h时间点对4种肺癌细胞的抑制作用,分别计算IC_(50)及细胞存活率,比较NXGH及NXGF对不同肺癌细胞的敏感性。结果:NXGH作用下,PC9、H358、H520、H1975肺癌细胞IC_(50)分别是0.675μmo L·L~(-1)、12.097μmo L·L~(-1)、11.368μmo L·L~(-1)和0.981μmo L·L~(-1),NXGH浓度为1.25、2.5和5μmo L·L~(-1)时,PC9和H1975细胞的IC_(50)低于H358和H520(P<0.05)。NXGF作用下,PC9、H358、H520、H1975肿瘤细胞IC_(50)分别是0.685μmo L·L~(-1)、4.265μmo L·L~(-1)、3.097μmo L·L~(-1)和0.331μmo L·L~(-1),NXGF浓度为1.25、2.5μmo L·L~(-1)时,PC9和H1975的IC_(50)低于H358和H520(P<0.05)。结论:本实验室设计构建的新型小分子酪氨酸激酶抑制剂NXGH和NXGF对不同EGFR表达水平和突变状态的肺癌细胞均有较高亲和性,且低浓度时对EGFR突变型更敏感。
OBJECTIVE: To study the sensitivity of different small molecule tyrosine kinase inhibitors NXGH and NXGF to different EGFR expression levels and the mutation status of lung cancer cells, and to provide a reference for constructing EGFR molecular imaging probes. Methods: NXGH and NXGF, a novel small molecule tyrosine kinase inhibitor based on NXG, were constructed. Four different EGFR expression levels and mutations were selected for lung cancer cells: PC9 (EGFR 19 exon deletion mutation), H1975 (EGFR L858R mutation combined T790M second mutation), H358 (EGFR wild-type) and H520 (EGFR negative). MTT assay was used to analyze the inhibitory effect of NXGH and NXGF for 48h on four kinds of lung cancer cells. IC 50 and Cell survival rate, compare NXGH and NXGF sensitivity of different lung cancer cells. Results: The IC 50 of PC9, H358, H520 and H1975 lung cancer cells were respectively 0.675μmo L·L -1, 12.097μmo L·L -1 and 11.368μmo L·L -1 IC 50 of PC9 and H1975 cells were lower than those of H358 and H520 cells (P <0.01) when the concentration of NXGH was 1.25, 2.5 and 5 μmol L·L -1 and 0.981μmo L·L -1, 0.05). Under the action of NXGF, the IC 50 of PC9, H358, H520 and H1975 tumor cells were 0.685μmol L·L -1, 4.265μmol L·L -1, 3.097μmol L·L -1 IC 50 of PC9 and H1975 were lower than those of H358 and H520 (P <0.05) when the concentration of NXGF was 1.25 or 2.5μmo L · L -1. Conclusion: The novel small molecule tyrosine kinase inhibitors NXGH and NXGF designed in our laboratory have higher affinity to lung cancer cells with different EGFR expression levels and mutations, and are more sensitive to EGFR mutation at low concentration.