Radiosensitivity of tumor cell lines after pretreatment with the EGFR tyrosine kinase inhibitor ZD1839 (Iressa®)
Radiosensitivity of tumor cell lines after pretreatment with the EGFR tyrosine kinase inhibitor ZD1839 (Iressa®)
复制标题
DOI：
10.1007/s00066-005-1319-5
复制
发表时间：
2005-03-01
影响因子：
3.1
通讯作者：
Rübe, C
中科院分区：
文献类型：
--
作者：
Burdak-Rothkamm, S;Rübe, CE;Rübe, C
背景和目的：表皮生长因子受体(EGFR)酪氨酸激酶抑制剂ZD1839(易瑞沙(R))可降低存活率。并增强某些肿瘤细胞的辐射反应。本研究的目的是确定与ZD1839调节放射敏感性相关的细胞事件。材料和方法：对三种肿瘤细胞株(A549、H596、FaDu)进行电离辐射照射、ZD1839处理和联合处理。克隆形成细胞存活率测定采用集落形成试验，EGFR和转化生长因子-α表达测定采用实时定量逆转录-聚合酶链式反应(RT-PCR)。结果：在A549和H596细胞中，ZD1839对克隆生长几乎没有影响，但存活曲线显示5mU M ZD1839对A549细胞具有放射增敏作用。两种细胞系均表达中等水平的EGFR mRNA和极低水平的转化生长因子-αmRNA。1 mU M ZD1839及其联合作用后，FADu细胞表达较高的EGFR和转化生长因子-α，并表现出明显的克隆性生长抑制、S期细胞减少和诱导细胞凋亡。令人惊讶的是，在ZD1839预处理后存活的FaDu细胞的亚细胞突变更具辐射抗性。ZD1839可导致A549细胞EGFR mRNA表达下降，H596细胞无变化，FADu细胞表达增加。结论：ZD1839对ZD1839的敏感性与其EGFR表达水平、抑制细胞增殖和诱导细胞凋亡有关。ZD1839的放射增敏作用与下调EGFR基因表达有关。
Background and Purpose: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa (R)) reduces survival. and augments radiation response of certain tumor cells. The aim of this study was to identify cellular events that are associated with the modulation of radiosensitivity by ZD1839.Material and Methods: Three tumor cell tines (A549, H596, FaDu) were exposed to ionizing radiation, treatment with ZD1839, and combined treatment. Clonogenic cell survival was determined by colony assays, EGFR and transforming growth factor-(TGF-)alpha expression by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), cell. cycle distribution and apoptosis by flow cytometry.Results: In A549 and H596 cells ZD1839 had little effect on clonogenic growth, but survival curves revealed a radiosensitizing effect of 5 mu M ZD1839 on A549 cells. Both cell lines expressed moderate amounts of EGFR mRNA and very tow levels of TGF-alpha mRNA. FaDu cells expressed relatively high amounts of EGFR and TGF-alpha transcripts and showed marked inhibition of clonogenic growth, reduction of S-phase cells, and induction of apoptosis after treatment with 1 mu M ZD1839 and combined treatment. Surprisingly, the subpoputation of FaDu cells surviving ZD1839 pretreatment was more radioresistant. Exposure to ZD1839 caused a decrease in EGFR mRNA expression in A549 cells, no change in H596, and even an increase in FaDu cells.Conclusion: The sensitivity to ZD1839 correlated with the EGFR expression Level, an inhibition of cell proliferation, and induction of apoptosis in the cell tines analyzed. A radiosensitizing effect of ZD1839 was associated with downregulation of EGFR mRNA expression.