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ID 53005
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Author
Yasugi, Masayuki
Takigawa, Nagio
Ochi, Nobuaki
Harada, Daijiro
Ninomiya, Takashi
Murakami, Toshi
Honda, Yoshihiro
Ichihara, Eiki
Abstract
Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1 mm in the everolimus-treated and control groups were 1.9 +/- 0.9 and 9.4 +/- 3.2 (t-test, p<0.001), respectively. pS6 was suppressed during everolimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation.
Keywords
Non-small cell lung cancer
Adenocarcinoma
Everolimus
mTOR
EGFR
Published Date
2014-08-15
Publication Title
Experimental Cell Research
Volume
volume326
Issue
issue2
Start Page
201
End Page
209
ISSN
0014-4827
Content Type
Journal Article
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/52961
language
英語
Copyright Holders
(c) 2014 Elsevier Inc. All rights reserved.
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author
Refereed
True
DOI
Web of Sience KeyUT