EGFRTKIs联合化疗的给药顺序对NSCLC细胞促凋亡的影响  

Effect of EGFR-TKIs and chemotherapy combinations and administration sequence on apoptosis of NSCLC cells

作　　者：高峰[1] 张泽峰[1] 王涛[1] 王瑞[1] Feng Gao;Ze-feng Zhang;Tao Wang;Rui Wang(First Department of Thoracic Surgery,the Fourth Hospital of Hebei Medical University,Shijiazhuang,Hebei 050011,China)

机构地区：[1]河北医科大学第四医院胸外一科,河北石家庄050011

出　　处：《中国现代医学杂志》2018年第14期24-30,共7页China Journal of Modern Medicine

摘　　要：目的探究表皮生长因子受体络氨酸激酶抑制剂(EGFR TKIs)与化疗药物单用、联用,以及顺序给药时,对获得性TKI耐药的非小细胞肺癌(NSCLC)细胞系凋亡的影响。方法选用存在TKI耐药基因突变(T790M,c MET)的NSCLC细胞系PC9ER、H1975和HCC827GR,以及TKI敏感基因突变(19外显子突变)的细胞系PC9和HCC827。采用MTS法检测化疗药物顺铂和紫杉醇,以及TKI厄洛替尼单用、联用,或者顺序给药干预各NSCLC细胞系时的细胞活性状态,并利用集落形成试验加以验证。采用Western blot检测各处理组蛋白裂解液中细胞凋亡标志物c PARP含量变化。结果 MTS法和集落形成试验结果发现,EGFR TKIs联合化疗能协同增加NSCLC细胞系的细胞毒性。同时给予EGFR TKIs和化疗或先化疗再用EGFR TKIs,可获得最佳干预效果。Western bolt检测结果表明,联合用药后c PARP蛋白表达升高。而且先化疗后EGFR TKIs干预比两者顺序颠倒的促凋亡作用更强。结论先化疗后EGFR TKIs干预的最优给药顺序可使对获得性TKI耐药的NSCLC细胞系产生最强的促凋亡作用。Objective To explore the effect of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)and chemotherapeutic drug alone,concurrent and sequential administration on apoptosis of non-small cell lung cancer(NSCLC)cells with acquired TKI-resistance.Methods NSCLC cell lines with TKI-resistance gene mutations(T790M and cMET)such as PC9ER,H1975 and HCC827GR as well as TKI-sensitive gene mutation(exon 19)cell lines PC9 and HCC827 were selected.Cell viability was detected by MTS assay when chemotherapy drugs Cisplatin,Paclitaxel and TKI Erlotinib were used alone,in combination or in sequential administration for intervention of NSCLC cell lines,and verified using colony formation assay.The content of apoptosis marker cPARP in cell lysate was detected in each treatment group by Western blot.Results MTS assay and colony formation revealed that the combination of EGFR-TKIs and chemotherapeutic drugs could synergistically increase the cytotoxicity to NSCLC cell lines.Simultaneous use of EGFR-TKIs and chemotherapeutic drugs or chemotherapy followed by EGFR-TKIs provided the maximum intervention.Western blot showed that the apoptotic marker cPARP expression was significantly increased when two drugs were simultaneously used.Moreover,chemotherapy HRPthen EGFR-TKIs intervention could obtain a more powerful pro-apoptotic performance than the reverse order intervention.Conclusions The sequence of chemotherapy followed by EGFR-TKI is likely to be the most active strategy,and could have the greatest effect on apoptosis in cell lines with acquired TKI-resistance.

关 键 词：非小细胞肺癌 获得性耐药 化疗 表皮生长因子受体络氨酸激酶抑制剂 

分 类 号：R734.2[医药卫生—肿瘤]