表皮生长因子受体酪氨酸激酶抑制剂ZD1839与奥沙利铂联合对人肺癌A549细胞的作用  

Cytotoxic Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Combination with Oxaliplatin on Lung Cancer Cell Line A549

作　　者：赵传华[1] 袁守军[2] 王岩[1] 葛飞娇[1] 罗卫东[1] 徐建明[1] 

机构地区：[1]军事医学科学院附属医院消化肿瘤内科,北京100071 [2]军事医学科学院放射医学研究所,北京100850

出　　处：《癌症》2007年第12期1299-1303,共5页Chinese Journal of Cancer

基　　金：全军"十一五"科技攻关项目(No.06G140)~~

摘　　要：背景与目的:ZD1839是一种表皮生长因子受体酪氨酸激酶的小分子抑制剂,是目前肺癌分子靶向治疗中较为成熟的药物,因其单药临床有效率低,如何与化疗联合提高抗癌效应受到关注。本实验通过研究ZD1839联合奥沙利铂的不同给药方案对人肺腺癌细胞A549的杀伤作用,探讨两药联合的最佳模式。方法:以药物联合效应测定方法,评价ZD1839和奥沙利铂不同给药顺序对A549细胞的抑制作用,以流式细胞仪测定不同联合方案对A549细胞周期分布及凋亡率的影响。观察ZD1839、奥沙利铂不同给药方案作用时,裸鼠A549细胞移植瘤生长情况,测定肿瘤生长抑制率。结果:先奥沙利铂后ZD1839的序贯给药方案表现出明显的协同作用,药物联合指数为0.51±0.01;而先ZD1839后给予奥沙利铂时,药物联合指数为1.56±0.03,两药间为拮抗作用。先奥沙利铂后ZD1839组G2/M期细胞比例与其他组相比明显增加,达到37.9%(P<0.05),细胞凋亡率达到22.3%。体内实验表明,先奥沙利铂后ZD1839组抑瘤率最高,达到58.9%;而先奥沙利铂+ZD183924h后ZD183948h组的抑瘤率为52.4%,ZD1839后奥沙利铂组的抑瘤率为30.6%。结论:先奥沙利铂后ZD1839序贯给药对A549细胞增殖的抑制作用更强。BACKGROUND ＆ OBJECTIVE： ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TKI）, has clinical antitumor activity, but its efficacy is low. This study was to assess the effects of ZD1839 in combination with oxaliplatin on lung adenocarcinoma cell line A549, and to provide pre-clinical evidence for optimizing the schedule of oxaliplatin combined with ZD1839. METHODS. Chou and Talalay method was used to analyze the combination effects of sequencing ZD1839 and oxaliplatin on A549 cells. Cell cycle distribution and cell apoptosis were analyzed by flow cytometry. The effects of oxaliplatin combined with ZD1839 on the proliferation of A549 cells in nude mice were also evaluated. RESULTS： Sequential oxaliplatin followed by ZD1839 produced synergistic effect, with a combination index （CI） of 0.51±0.01. In contrast, ZD1839 followed by oxaliplatin exhibited antagonist effect, with a CI of 1.56±0.03, Compared with other sequences, oxaliplatin followed by ZD1839 induced more cells being arrested in G2/M phase （37.9%, P〈0.05）; the apoptosis rate was 22.3%. The inhibition rate of tumor growth in nude mice was 58.9% when treated with oxaliplatin followed by ZD1839, 52.4% when treated with oxaliplatin and ZD1839 for 24 h and followed by ZD1839 for additional 48 h, and 30.6% when treated with ZD1839 followed by oxaliplatin. CONCLUSION： Sequential oxaliplatin followed by ZD1839 has the maximal inhibitory effect on the proliferation of A549 cells.

关 键 词：肺肿瘤 A549细胞 表皮生长因子受体 ZD1839 奥沙利铂 联合用药 抑瘤作用 裸鼠 

分 类 号：R734.2[医药卫生—肿瘤]