Takada Yasunari, Matsuo Koichi
Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
Keio J Med. 2012;61(4):120-7. doi: 10.2302/kjm.2011-0009-oa.
Gefitinib is an anticancer drug developed to inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Two structurally-related EGFR tyrosine kinase inhibitors, gefitinib (Iressa) and erlotinib (Tarceva), are used as oral chemotherapy by patients with non-small-cell lung cancer. Immediately after introduction of gefitinib to clinical practice, interstitial lung disease was identified as a life-threatening adverse effect, although this condition can be well managed. It is still unclear whether gefitinib and other EGFR inhibitors induce similar adverse effects in lung. We previously established mouse models of interstitial lung disease in which gefitinib induces expression of Fosl1 (which encodes the AP-1 transcription factor Fra-1) in the presence of exogenous or endogenous Toll-like receptor ligands, leading to abnormal cytokine and chemokine expression. Here, we compared and monitored the effects of EGFR inhibitors gefitinib, erlotinib and AG1517 (PD153035) on the mRNA expression levels of Fosl1, Tnf and Ccl2. Unexpectedly, gefitinib, but not the other tyrosine kinase inhibitors, elicited the Fosl1 expression profile proposed to be predictive of interstitial lung disease, suggesting that gefitinib-induced interstitial lung disease is an off-target effect not elicited by erlotinib.
吉非替尼是一种开发用于抑制表皮生长因子受体（EGFR）酪氨酸激酶活性的抗癌药物。两种结构相关的EGFR酪氨酸激酶抑制剂，吉非替尼（易瑞沙）和厄洛替尼（特罗凯），被非小细胞肺癌患者用作口服化疗药物。吉非替尼引入临床实践后不久，间质性肺病就被确定为一种危及生命的不良反应，尽管这种情况可以得到很好的控制。吉非替尼和其他EGFR抑制剂是否会在肺部诱发类似的不良反应仍不清楚。我们之前建立了间质性肺病小鼠模型，在该模型中，吉非替尼在外源性或内源性Toll样受体配体存在的情况下诱导Fosl1（编码AP-1转录因子Fra-1）表达，导致细胞因子和趋化因子表达异常。在此，我们比较并监测了EGFR抑制剂吉非替尼、厄洛替尼和AG1517（PD153035）对Fosl1、Tnf和Ccl2 mRNA表达水平的影响。出乎意料的是，吉非替尼而非其他酪氨酸激酶抑制剂引发了被认为可预测间质性肺病的Fosl1表达谱，这表明吉非替尼诱导的间质性肺病是一种厄洛替尼未引发的脱靶效应。
