Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells.
Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells.
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DOI：
10.1038/sj.bjc.6601504
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发表时间：
2004-01-12
影响因子：
8.8
通讯作者：
Sonoo, H
中科院分区：
文献类型：
--
作者：
Okubo, S;Kurebayashi, J;Otsuki, T;Yamamoto, Y;Tanaka, K;Sonoo, H
表皮生长因子受体（EGFR）/HER 1的高表达水平已被认为导致乳腺癌患者的生存时间缩短和对内分泌治疗的抵抗。为了检验抑制EGFR信号通路影响内分泌治疗的抗肿瘤作用的假设，将EGFR酪氨酸激酶抑制剂（EGFR-TKI）吉非替尼和雌激素受体（ER）拮抗剂氟维司群给予人乳腺癌细胞。总共使用了五种人乳腺癌细胞系。分析吉非替尼和/或氟维司群单独或联合治疗对细胞生长、细胞周期进展和细胞凋亡的影响。还研究了细胞周期蛋白依赖性激酶抑制剂p21和p27、抗凋亡因子Bcl-2和促凋亡因子Bax表达水平的变化。所有检测的细胞系均对吉非替尼敏感（50%生长抑制浓度，10-28.5 μM）。HER 1或HER 2高表达的乳腺癌细胞系对吉非替尼的敏感性高于其他细胞系。吉非替尼在ER阳性KPL-3C细胞中诱导显著的G1-S阻断。吉非替尼在HER 1过表达的MDA-MB-231细胞中诱导显著的凋亡。在添加17β-雌二醇的培养基中，吉非替尼可额外增加氟维司群在所有三种ER阳性细胞系中的抗肿瘤作用。联合治疗促进了KPL-3C细胞的细胞周期阻滞，这分别与氟维司群和吉非替尼上调p21相关。MDA-MB-231细胞凋亡与吉非替尼下调Bcl-2相关。这些结果表明，在ER阳性乳腺癌细胞中，EGFR-TKI吉非替尼和抗雌激素氟维司群之间存在叠加相互作用。
A high expression level of epidermal growth factor receptor (EGFR)/HER1 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer. To test the hypothesis that inhibition of the EGFR signalling pathway affects the antitumour effect of endocrine therapy, an EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, and an oestrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. A total of five human breast cancer cell lines were used. The effects of single or combined treatments with gefitinib and/or fulvestrant on cell growth, cell cycle progression and apoptosis were analysed. Changes in the expression levels of cyclin-dependent kinase inhibitors, p21 and p27, an antiapoptotic factor, Bcl-2, and a proapoptotic factor, Bax, were also investigated. All cell lines tested were sensitive to gefitinib (50% growth inhibitory concentration, 10–28.5 μM). Breast cancer cell lines with a high expression level of HER1 or HER2 were more sensitive to gefitinib than the others. Gefitinib induced a significant G1–S blockade in ER-positive KPL-3C cells. Gefitinib induced significant apoptosis in HER1-overexpressing MDA-MB-231 cells. Gefitinib additively increased the antitumour effect of fulvestrant in all three ER-positive cell lines in a medium supplemented with 17β-oestradiol. The combined treatment promoted cell cycle retardation in KPL-3C cells, which is associated with an upregulation of p21 by fulvestrant and gefitinib, respectively. Apoptosis was associated with downregulation of Bcl-2 by gefitinib in MDA-MB-231 cells. These results suggest an additive interaction between the EGFR-TKI gefitinib and the antioestrogen fulvestrant in ER-positive breast cancer cells.