title: Gefitinib, but not erlotinib, is a possible inducer of Fra-1-mediated interstitial lung disease.
abstract: 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.
authors: Laboratory of Cell and Tissue Biology, School of Medicine, Keio University,           Tokyo, Japan.
authors: Yasunari
authors: Y
authors: Takada
authors: Koichi
authors: K
authors: Matsuo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D017563:Lung Diseases, Interstitial / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000009:adverse effects* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D000970:Antineoplastic Agents; D018932:Chemokine CCL2; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011799:Quinazolines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000099169:Fos-Related Antigen 1; C491768:Ccl2 protein, mouse; C541485:EGFR protein, mouse; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline