Elucidation of mechanism of drug eruption due to epidermal growth factor receptor tyrosine kinase inhibitors

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591319
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Nagoya University
• Principal Investigator: SUGIURA Kazumitsu 名古屋大学, 大学院・医学系研究科, 准教授 (70335032)
• Co-Investigator(Kenkyū-buntansha): MURO Yoshinao 名古屋大学, 大学院・医学系研究科, 准教授 (80270990)
• Project Period (FY): 2008 – 2010
• Keywords: 上皮成長因子受容体チロシンキナーゼ阻害薬 / 薬疹 / CCL2 / CCL5 / IL-1 / IL-1R2 / 発症メカニズム

Research Abstract

Epidermal growth factor receptor tyrosine kinase(EGFR-TK) is a transducer of mitogenic signals, and is involved in the pathogenesis and progression of a number of cancers, including non-small cell lung cancer(NSCLC). Gefitinib is an EGFR-TK inhibitor that is clinically used to treat NSCLC ; however, this drug frequently causes adverse effects, including skin eruptions. The mechanism underlying these skin reactions is elusive, although it is assumed that they are caused by the inhibition of EGFR-TK signaling in epidermal and adnexal cells. In this study, we demonstrate that IL-1-mediated signaling is activated to induce the high expression of CCL2 and CCL5 via reduction of IL-1R2 in the skin lesions caused by gefitinib.

Research Products

• [Journal Article] Overexpression of LEDGF/DFS70 induces IL-6 via p38 activation in HaCaT cells which is similar to that seen in the psoriatic condition (2010)
  • Author(s): Takeichi T, Sugiura K, Muro Y, Matsumoto K, Ogawa Y, Futamura K, Kaminuma O, Hashimoto N, Shimoyama Y, Saito H, Tomita Y.
  • Journal Title: J Invest Dermatol Volume: 130 Pages: 2760-2767
  • Peer Reviewed
• [Journal Article] Epidermal growth factor receptor trosine kinase inhibitors induce CCL2 and CCL5 via reduction in IL-1R2 in keratinocytes (2010)
  • Author(s): Yamaki M, Sugiura K, Muro Y, Shimoyama Y, Tomita Y.
  • Journal Title: Exp Dermatol Volume: 19(8) Pages: 730-5
  • Peer Reviewed
• [Journal Article] Anti-MDA5 and anti-TIF1γantibodies have clinical significance for patients with dermatomyositis. (2010)
  • Author(s): Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T.
  • Journal Title: Rheumatology(Oxford) Volume: 49(9) Pages: 1726-33
  • Peer Reviewed
• [Journal Article] エトレチナートが有効であった小児膿疱性乾癬 (2010)
  • Author(s): 渡邉奏子, 杉浦一充, 富田靖
  • Journal Title: 皮膚病診療 Volume: 32巻11号 Pages: 1195-1198
• [Journal Article] 掻痒性皮膚疾患に対する第2世代抗ヒスタミン薬の有効性・安全性クロスオーバー法を用いた比較検討 (2010)
  • Author(s): 杉浦一充, 満間照之, 横田雅史, 清水真, 鈴木信吾, 新田悠紀子, 稲垣克彦, 臼田俊和, 工藤清孝, 富田靖
  • Journal Title: Progress in Medicine Volume: 30巻7号 Pages: 1997-2001
• [Journal Article] インフリキシマブが著効した小児膿疱性乾癬 (2010)
  • Author(s): 松本朋子, 杉浦一充, 富田靖
  • Journal Title: 皮膚病診療 Volume: 32巻2号 Pages: 171-174
• [Journal Article] The Unfolded Protein Response Is Activated in Differentiating Epidermal Keratinocytes (2009)
  • Author(s): Sugiura K, Muro Y, Futamura K, Matsumoto K, Hashimoto N, Nishizawa Y, Nagasaka T, Saito H, Tomita Y, Usukura J.
  • Journal Title: J Invest Dermatol Volume: 129 Pages: 2126-2135
• [Journal Article] An evaluation of the efficacy of the toe brachial index measuring vascular involvement in systemic sclerosis and other connective tissue diseases (2009)
  • Author(s): Muro Y, Sugiura K, Morita Y Tomita Y
  • Journal Title: Clin Exp Rheumatol. Volume: 27 Pages: 26-31
  • Peer Reviewed
• [Journal Article] Evaluation of anti-ribosomal P protein immnoassays in Japanese patients with connective tissue diseases in comparison to indirect immunofluorescence assays (2009)
  • Author(s): Muro Y, Sugiura K, Morita Y, Tomita Y
  • Journal Title: Scand J Rheumatol. Volume: 38 Pages: 460-463
  • Peer Reviewed
• [Journal Article] Scoring of reflux symptoms associated with scleroderma and the usefulness of rabeprazole (2009)
  • Author(s): Muro Y, Sugiura K, Nitta Y, Mitsuma T, Hoshino K, Usuda T, Hayashi K, Murase Y, Shimizu M, Matsuo H
  • Journal Title: Clin Exp Rheumatol. Volume: 27 Pages: 15-21
  • Peer Reviewed
• [Journal Article] Successful topical hemotherapy with a new occlusive dressing for an intractable ulcer on the toe (2009)
  • Author(s): Iwayama-Hibino M, Sugiura K, Muro Y, Tomita Y.
  • Journal Title: J Dermatol Volume: 36 Pages: 245-8
  • Peer Reviewed
• [Journal Article] CENP-O, a protein localized at the centromere throughout the cell cycle, is a novel target antigen in systemic sclerosis. (2009)
  • Author(s): Saito A, Muro Y, Sugiura K, Ikeno M, Yoda K, Tomita Y.
  • Journal Title: J Rheumatol. Volume: 36 Pages: 781-6
  • Peer Reviewed
• [Journal Article] Sweet病関節炎を伴った症例 (2009)
  • Author(s): 新田悠紀子, 杉浦一充
  • Journal Title: Visual Dermatology Volume: 9巻1号 Pages: 50-52
• [Journal Article] SLEの経過中にStevens Johnson症候群進展型中毒性表皮壊死症を呈した1例 (2009)
  • Author(s): 柴田章貴, 杉浦一充, 奥田容子, 室慶直, 富田靖, 八島章仁
  • Journal Title: 臨床皮膚科 Volume: 63巻4号 Pages: 282-285
  • Peer Reviewed
• [Journal Article] Anti-SS-A/Ro antibody determination by indirect immunofluorescence and comparison of different methods of antinuclear antibody screening : Evaluation of the utility of HEp-2 cells transfected with the 60 kDa SS-A/Ro as a substrate (2008)
  • Author(s): Tanaka N., Muro Y., Sugiura K., and Tomita Y.
  • Journal Title: Modern Rheum Volume: 18(6) Pages: 585-92
  • Peer Reviewed
• [Journal Article] Anti-cyclic citrullinated peptide antibody in systemic sclerosis (2008)
  • Author(s): Morita Y., Muro Y., Sugiura K., Tomita Y.
  • Journal Title: Clin Exp Rheumatol Volume: 26(4) Pages: 542-7
  • Peer Reviewed
• [Journal Article] Comparison of ELISA with CENP-A and CENP-B for the detection of anti-centromere (2008)
  • Author(s): Hoshino K., Muro Y., Sugiura K., Tomita Y.
  • Journal Title: Clin Exp Rheumatol Volume: 26(3) Pages: 505
  • Peer Reviewed
• [Journal Article] Evaluation of cetirizine hydrochloride-based therapeutic strategy for chronic urticaria (2008)
  • Author(s): Sugiura K, Hirai S, Suzuki T, Usuda T, KondoT, Azumi T, Masaki S, Yokoi T, Nitta Y, Kamiya S, Ando K, Mori T, Tomita Y
  • Journal Title: Nagoya J Med Sci. Volume: 70(3-4) Pages: 97-106
  • Peer Reviewed
• [Journal Article] High concomitance of disease marker autoantibodies in anti-DFS70/LEDGF antibody-positive. patients with autoimmune rheumatic disease. (2008)
  • Author(s): Muro Y., Sugiura K., Morita Y., Tomita Y.
  • Journal Title: Lupus Volume: 17 Pages: 171-6
  • Peer Reviewed
• [Journal Article] ミュンヒハウゼン症候群による自傷行為で発症した壊死性筋膜炎の1例 (2008)
  • Author(s): 梶田直美, 杉浦一充, 澤田昌樹, 横田憲二, 富田靖
  • Journal Title: 臨床皮膚科 Volume: 62巻13号 Pages: 991-994
  • Peer Reviewed
• [Journal Article] Churg-Shtrauss症候群 (2008)
  • Author(s): 山崎有子, 杉浦一充, 富田靖
  • Journal Title: 皮膚病診療 Volume: 30巻11号 Pages: 1229-1232
• [Journal Article] 鞍鼻から診断された第3期梅毒の1例 (2008)
  • Author(s): 梶田直美, 杉浦一充, 中田誠一, 富田靖
  • Journal Title: 皮膚科の臨床 Volume: 50巻10号 Pages: 1251-1254
  • Peer Reviewed
• [Presentation] Overexpression of LEDGF/DFS70 induces IL-6 via p38 activation in HaCaT cells, which resembles psoriasis. (2010)
  • Author(s): Takeichi T, Sugiura K, Muro Y, Matsumoto K, Ogawa Y, Futamura K, Tomita Y
  • Organizer: 40^<th> annual ESDR meeting
  • Place of Presentation: Helsinki
  • Year and Date: 20100900
• [Presentation] Epidermal growth factor receptor tyrosine kinase inhibitors induce CCL2 and CCL5 via reduction of type II interleukin-1 receptor in keratinocytes. (2010)
  • Author(s): Sugiura K, Yamaki M, Muro Y, Tomita Y
  • Organizer: 14^<th> international congress of mmunology
  • Place of Presentation: Kobe
  • Year and Date: 20100800
• [Presentation] Overexpression of LEDGF/DFS70 induces IL-6 via p38 activation in HaCaT cells which is similar to psoriatic condition (2010)
  • Author(s): Takeichi T, Sugiura K, Muro Y, Matsumoto K, Ogawa Y, Futamura K, Tomita Y
  • Organizer: 14^<th> international congress of mmunology
  • Place of Presentation: Kobe
  • Year and Date: 20100800
• [Presentation] Epidemiologic study of anti-melanoma differentiation-associate gene 5(MDA-5) autoantibodies-a major autoimmune response in amyopathic dermatomyositis. (2010)
  • Author(s): Muro Y, Hoshino K, Sugiura K, Tamakoshi K
  • Organizer: 14^<th> international congress of mmunology
  • Place of Presentation: Kobe
  • Year and Date: 20100800
• [Presentation] IgE class autoantibody against DFS70/LEDGF in atopic dermatitis (2010)
  • Author(s): Watanabe K, Muro Y, Sugiura K, Tomita Y
  • Organizer: 14^<th> international congress of mmunology
  • Place of Presentation: Kobe
  • Year and Date: 20100800
• [Presentation] nti-DFS(dense fine speckled) 70 antibody in patients with atopic dermatitis (2010)
  • Author(s): Higashi N, Sugiura K, Muro Y
  • Organizer: International symoposium on atopic dermatitis 2010
  • Place of Presentation: Munchen
  • Year and Date: 20100700
• [Presentation] Examination of Gene Expression Profiles in Hair Root Tissue Provides Useful Local Information (2009)
  • Author(s): Yagami A, Matsumoto K, Futamura K, Matsuda A, Orihara K, Hashimoto N, Kojima R, Morita H, Sugiura K, Muro Y, Tomita Y, Matsunaga K, Saito H
  • Organizer: American Academy of Allergy Asthma & Immunology
  • Year and Date: 20090500
• [Presentation] The unfolded protein response is activated in differentiationg keratinocytes (2009)
  • Author(s): Sugiura K, Muro Y, Futamura K Matsumoto K Hashimoto N Nishizawa Y, Nagasaka T, Saito H, Usukura J Tomita Y
  • Organizer: The 4th Joint Meeting of Japanese Dermatological Association and Australasian College of Dermatologists
  • Place of Presentation: Sapporo
  • Year and Date: 2009-07-11
• [Presentation] The unfolded protein response is involved in epidermal keratinocyte differentiation (2008)
  • Author(s): Sugiura K, Muro Y, Futamura K, Matsumoto K, Hashimoto N, Nishizawa Y, Nagasaka T, Saito H, Usukura J, Tomita Y
  • Organizer: The International Investigative Dermatology 2008
  • Place of Presentation: Kyoto
  • Year and Date: 20080514-17
• [Presentation] LEDGF/DFS70, A Major Autoantigen of Atopic Dermatitis, Is a Component of Keratohyalin Granules 5th Georg Rajka (2008)
  • Author(s): Sugiura K
  • Organizer: Symposium on Atopic Dermatitis
  • Place of Presentation: Kyoto
  • Year and Date: 20080511-13
• [Remarks] ホームページ
  • URL: http://www.med.nagoya-u.ac.jp/derma/
• [Patent(Industrial Property Rights)] ADM抗体エピトープペプチドおよびその利用 (2009)
  • Inventor(s): 石井陽子、松尾克彦、丹羽幹夫、室慶直、杉浦一充
  • Industrial Property Rights Holder: 石井陽子、松尾克彦、丹羽幹夫、室慶直、杉浦一充
  • Industrial Property Number: 特許、特願2009-119306
  • Filing Date: 2009-05-15