Schedule-dependent antitumor activity of the combination with erlotinib and docetaxel in human non-small cell lung cancer cells with EGFR mutation, KRAS mutation or both wild-type EGFR and KRAS
Schedule-dependent antitumor activity of the combination with erlotinib and docetaxel in human non-small cell lung cancer cells with EGFR mutation, KRAS mutation or both wild-type EGFR and KRAS
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DOI：
10.3892/or_00000965
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发表时间：
2010-11-01
期刊：
影响因子：
4.2
通讯作者：
Mori, Kazushige
中科院分区：
文献类型：
--
作者：
Furugaki, Koh;Iwai, Toshiki;Mori, Kazushige
厄洛替尼被用作复发性晚期非小细胞肺癌（NSCLC）的标准治疗。NSCLC中表皮生长因子受体（EGFR）突变已被证明是厄洛替尼的预测因素，尽管K-ras癌基因（KRAS）突变与厄洛替尼耐药之间的关系存在争议。最近，厄洛替尼和多西他赛的体外序列依赖性相互作用已被研究作为一种新的治疗NSCLC的方法。本研究的目的是确定厄洛替尼和多西他赛对具有EGFR突变（HCC 827细胞）、KRAS突变（A549细胞）或两者均为野生型（NCI-H292细胞）的NSCLC细胞的最佳新方案。首先，我们使用组合指数分析了体外组合对细胞增殖抑制的作用。在所有细胞系中，多西他赛随后厄洛替尼治疗显示出几乎累加效应。另一方面，厄洛替尼随后多西他赛治疗显示出显著的拮抗相互作用。其次，我们检查了组合对体外凋亡诱导的影响。与多西他赛单药治疗相比，厄洛替尼联合多西他赛治疗可降低细胞凋亡诱导;相反，多西他赛联合厄洛替尼治疗对任何细胞系中多西他赛诱导的细胞凋亡均无抑制作用。最后，使用异种移植模型进行体内肿瘤生长抑制试验。在所有模型中，与厄洛替尼或多西他赛单药治疗相比，多西他赛随后厄洛替尼给药导致显著的肿瘤生长抑制。总之，我们证明，无论EGFR和KRAS的突变状态如何，多西他赛联合厄洛替尼治疗都是治疗NSCLC的潜在最佳方案。
Erlotinib is used as a standard treatment for recurrent advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations in NSCLC have been shown to be a predictive factor of erlotinib, although the relationship between K-ras oncogene (KRAS) mutations and erlotinib resistance is controversial. Recently, in vitro sequence-dependent interactions of erlotinib and docetaxel have been studied on as a novel therapeutic approach against NSCLC. The purpose of the present study was to determine the optimum novel regimen of erlotinib and docetaxel against NSCLC cells which have EGFR mutation (HCC827 cells), KRAS mutation (A549 cells) or both wild-type (NCI-H292 cells). First, we analyzed the effects of in vitro combination for cell proliferation-inhibition using a combination index. In all cell lines, docetaxel followed by erlotinib treatment showed nearly additive effects. On the other hand, erlotinib followed by docetaxel treatment showed remarkable antagonistic interactions. Second, we examined the effect of combinations on the in vitro apoptosis induction. Erlotinib followed by docetaxel treatment reduced apoptosis induction compared with docetaxel alone; in contrast, docetaxel followed by erlotinib treatment had no inhibitory effects on docetaxel-induced apoptosis in any of the cell lines. Finally, an in vivo tumor growth inhibition test was performed using xenograft models. Docetaxel followed by erlotinib administration resulted in significant tumor growth inhibition compared with erlotinib or docetaxel monotherapy in all models. In conclusion, we demonstrated that docetaxel followed by erlotinib therapy was a potentially optimum regimen against NSCLC regardless of the mutation status of EGFR and KRAS.