Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (′Iressa′) is independent of EGFR expression level
Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (′Iressa′) is independent of EGFR expression level
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DOI：
10.1002/jcp.10411
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发表时间：
2004-02-01
影响因子：
5.6
通讯作者：
Gianni, L
中科院分区：
文献类型：
--
作者：
Campiglio, M;Locatelli, A;Gianni, L
表皮生长因子受体（EGFR）在乳腺癌中的高表达赋予肿瘤细胞生长优势。EGFR酪氨酸激酶抑制剂（EGFR-TKI）ZD 1839（“易瑞沙”）在广泛的肿瘤类型中具有临床活性，尽管其发挥抗肿瘤活性作用的机制尚不清楚。我们分析了ZD 1839诱导乳腺癌细胞系凋亡和/或抑制增殖的能力，以及这种能力与MAPK和Akt（最近提出的ZD 1839活性标志物）下调活性之间的任何相关性。在表达不同水平EGFR和HER 2并暴露于ZD 1839的6种人乳腺癌细胞系中评价了Akt和MAPK的增殖、存活和活化。使用特异性单克隆抗体和FACS分析测定EGFR和HER 2表达水平。ZD 1839的作用与EGFR表达水平无关，但受高HER 2表达的影响。ZD 1839显著降低了四种敏感细胞系中[H-3]-胸苷掺入的速率，同时在其中两种细胞系中也诱导了细胞凋亡。在肿瘤细胞系中，ZD 1839的细胞抑制或细胞毒性作用与其下调MAPK和Akt活性的能力之间没有相关性。我们的数据表明，ZD 1839的抗肿瘤活性是由于细胞生长抑制作用，仅涉及敏感细胞亚群的凋亡诱导，MAPK和Akt均不是ZD 1839活性的可靠标志物。(C)2003 Wiley-Liss，Inc.
High expression of the epidermal growth factor receptor (EGFR) in breast carcinoma confers a growth advantage to the tumor cells. The EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 ('Iressa') has clinical activity in a wide range of tumor types, although the mechanism(s) by which it exerts its antitumor activity effects remain unclear. We analyzed the ability of ZD1839 to induce apoptosis and/or inhibition of proliferation in breast carcinoma cell lines, as well any association between this ability and the downregulation activity of MAPK and Akt, two recently proposed markers of ZD1839 activity. Proliferation, survival, and activation of Akt and MAPK were evaluated in six human breast cancer cell lines expressing various levels of EGFR and HER2 and exposed to ZD1839. EGFR and HER2 expression levels were determined using specific monoclonal antibodies and FACS analysis. The effects of ZD1839 were independent of EGFR expression levels, but were influenced by high HER2 expression. ZD1839 significantly reduced the rate of [H-3]-thymidine incorporation in the four sensitive cell lines, while apoptosis was also induced in two of these cell lines. No correlation was found between the cytostatic or cytotoxic effects of ZD1839 and its ability to downregulate MAPK and Akt activity in the tumor cell lines. Our data suggest that the antitumor activity of ZD1839 is due to a cytostatic effect, and involves apoptosis induction in a subset of sensitive cells only, and that neither MAPK nor Akt is a reliable marker of ZD1839 activity. (C) 2003 Wiley-Liss, Inc.