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ID 52842
フルテキストURL
著者
Murakami, Toshi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Takigawa, Nagio Kawasaki Med Univ, Dept Gen Internal Med 4
Ninomiya, Takashi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Ochi, Nobuaki Kawasaki Med Univ, Dept Gen Internal Med 4
Yasugi, Masaaki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Honda, Yoshihiro Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Kubo, Toshio Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Ichihara, Eiki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Hotta, Katsuyuki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Tanimoto, Mitsune Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Kiura, Katsuyuki Okayama Univ Hosp, Dept Allergy & Resp Med
抄録
Objective: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. Materials and methods: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MIT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. Results: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model: Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1 mm) in the AZD1480-treated group and control group were 0.37 +/- 0.18 and 2.25 +/- 0.53 (p <0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p <0.0001). Conclusion: AZD1480 may be effective against lung tumors driven by an activating EGER mutation.
キーワード
Lung cancer
Oncogene addiction
EGFR
JAK2
STAT3
Transgenic mice
発行日
2014-01
出版物タイトル
Lung Cancer
83巻
1号
出版者
Elsevier Ireland Ltd.
開始ページ
30
終了ページ
36
ISSN
0169-5002
NCID
AA10785743
資料タイプ
学術雑誌論文
関連URL
http://ousar.lib.okayama-u.ac.jp/metadata/52825
言語
English
OAI-PMH Set
岡山大学
著作権者
(C) 2013 Elsevier Ireland Ltd. All rights reserved.
論文のバージョン
author
査読
有り
DOI
Web of Sience KeyUT