表皮生长因子受体酪氨酸激酶抑制剂ZD1839联合奥沙利铂对肺癌细胞系A549的细胞毒性作用

[Cytotoxic effect of epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in combination with oxaliplatin on lung cancer cell line A549].

作者信息

Zhao Chuan-Hua, Yuan Shou-Jun, Wang Yan, Ge Fei-Jiao, Luo Wei-Dong, Xu Jian-Ming

机构信息

Department of Gastrointestinal Oncology, The Affiliated Hospital, Academy of Military Medical Sciences, Beijing, 100071, PR China.

出版信息

Ai Zheng. 2007 Dec;26(12):1299-303.

PMID:18076790

Abstract

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 G(2/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.

摘要

背景与目的

ZD1839是一种选择性表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），具有临床抗肿瘤活性，但疗效较低。本研究旨在评估ZD1839联合奥沙利铂对肺腺癌细胞系A549的影响，为优化奥沙利铂与ZD1839联合用药方案提供临床前依据。

方法

采用Chou和Talalay法分析ZD1839与奥沙利铂序贯给药对A549细胞的联合作用。通过流式细胞术分析细胞周期分布和细胞凋亡情况。还评估了奥沙利铂联合ZD1839对裸鼠体内A549细胞增殖的影响。

结果

奥沙利铂序贯ZD1839产生协同作用，联合指数（CI）为0.51±0.01。相比之下，ZD1839序贯奥沙利铂表现为拮抗作用，CI为1.56±0.03。与其他给药顺序相比，奥沙利铂序贯ZD1839诱导更多细胞阻滞于G(2/M)期（37.9%，P<0.05）；凋亡率为22.3%。奥沙利铂序贯ZD1839治疗裸鼠时肿瘤生长抑制率为58.9%，奥沙利铂与ZD1839同时处理24小时后再给予ZD1839 48小时的抑制率为52.4%，ZD1839序贯奥沙利铂治疗时抑制率为30.6%。