Mechanism of mTOR inhibitor-associated stomatitis
Project/Area Number |
15K11309
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Surgical dentistry
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Research Institution | Niigata University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
芳澤 享子 松本歯科大学, 歯学部, 教授 (60303137)
中田 光 新潟大学, 医歯学総合病院, 教授 (80207802)
武井 延之 新潟大学, 脳研究所, 准教授 (70221372)
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Research Collaborator |
IZUMI Kenzi
ITO Yuko
YAMAMOTO Youka
OHHASHI Riuko
HUJIMOTO Yoko
WATANABE Mari
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | mTOR阻害剤 / 口内炎 / 口腔粘膜細胞培養 / シロリムス / 有害事象 / 発症機序 / ヒト口腔粘膜上皮細胞培養 / リンパ脈管筋腫症 |
Outline of Final Research Achievements |
As a basic experiment in vitro for sirolimus stomatitis, oral mucosal cells were cultured from 7 passages to 8 passages. Sirolimus was added onto the cultured cells, and the reaction of the cultured cells was observed. As a result, the doubling time of cell proliferation was prolonged by 5 times at 10 nM compared to 0 nM. The DNA synthesis ability decreased by about 20%. The morphology was spindle-shaped and many large cells at 0 nM, and small spherical cells increased at 1 nM or more. The area of the nuclei was significantly smaller at 10 nM compared to sirolimus 0 nM. The area of the cells was significantly smaller at 0.1 nM, 1 nM and 10 nM compared to sirolimus 0 nM. Furthermore, the expression of E-Cadherin was suppressed, and cell-cell adhesion was weakened.
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Academic Significance and Societal Importance of the Research Achievements |
申請者らは、リンパ脈管筋腫症に対するmTOR阻害剤の日米加共同MILES試験の日本側代表として試験の成功に貢献し、ついで安全性確立を目的とした医師主導治験を実施し、LAMに対する世界初の薬事承認に繋げた。その後、結節性硬化症の血管線維腫に対する外用が承認された。現在、難治性リンパ管疾患、限局性皮質異形成II型のてんかん発作、進行性骨化性線維異形成症に対する医師主導治験が進行中であり、益々適応拡大が予想される。mTOR阻害剤により高頻度に発症する有害事象の一つに口内炎があり、患者のQOLを著しく低下させている。mTOR阻害剤による口内炎の発症機序の解明と治療・予防法の確立は喫緊の課題である。
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Report
(5 results)
Research Products
(18 results)
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[Journal Article] Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study.2017
Author(s)
Kitamura N, Seyama K, Inoue Y, Nagai K, Suzuki M, Moriyama H, Takada T, Tazawa R, Hirai T, Mishima M, Hayashida M, Hirose M, Arai T, Sugimoto C, Hattori N, Watanabe K, Tamada T, Akazawa K, Tanaka T, Nakata K.
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Journal Title
Pharmacoepidemiol Drug Saf.
Volume: 26
Pages: 1182-1189
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Efficacy and Safety of Long-Term Sirolimus Therapy for Asian Patients with Lymphangioleiomyomatosis.2016
Author(s)
Takada T, Mikami A, Kitamura N, Seyama K, Inoue Y, Nagai K, Suzuki M, Moriyama H, Akasaka K, Tazawa R, Hirai T, Mishima M, Hayashida M, Hirose M, Sugimoto C, Arai T, Hattori N, Watanabe K, Tamada T, Yoshizawa H, Akazawa K, Tanaka T, Yagi K, Young LR, McCormack FX, Nakata K
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Journal Title
Annals of the American Thoracic Society
Volume: 13
Pages: 1912-1922
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease.2016
Author(s)
Kuwahara S, Hosojima M, Kaneko R, Aoki H, Nakano D, Sasagawa T, Kabasawa H, Kaseda R, Yasukawa R, Ishikawa T, Suzuki A, Sato H, Kageyama S, Tanaka T, Kitamura N, Narita I, Komatsu M, Nishiyama A, Saito A.
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Journal Title
Journal of the American Society of Nephrology.
Volume: 27
Pages: 1996-2008
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] Risk Factors for Stomatitis in Patients with Lymphangioleiomyomatosis During Treatment with Sirolimus: A Multicenter Investigator-Initiated Prospective Study2017
Author(s)
Koh Nakata,Kuniaki Seyama,Yoshikazu Inoue,Toshinori Takada,Masaru Suzuki,Tsutomu Tamada,Toru Arai,Toyohiro Hirai,Tomohiro Handa,Chikatoshi Sugimoto,Nobutaka Kitamura,Ryushi Tazawa
Organizer
American Thoracic Society 2017 International Conference
Related Report
Int'l Joint Research
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[Presentation] Early and Late Onset Adverse Events in LAM Patients Treated with Sirolimus for Two Years2016
Author(s)
Nakata K, Inoue Y, Seyama K, Tazawa R, Tamada T, Mikami A, Nakayama H, Suzuki M, Ebina M, Hanaoka M , Hattori N, Hirai T, Arai T, Sugimoto C, Kitamura N, Tanaka T, Akazawa K, Mishima M
Organizer
ATS 2016
Place of Presentation
San Francisco(USA)
Year and Date
2016-05-17
Related Report
Int'l Joint Research
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[Presentation] Early Intervention with Sirolimus Benefits Mild Lymphangioleiomyomatosis-Related Lung Disease2016
Author(s)
Takada T, Seyama K, Inoue Y, Nagai K, Suzuki M, Moriyama H, Akasaka K, Tazawa R, Hirai T, Mishima M, Hayashida M, Hirose M, Sugimoto C, Arai T, Hattori N, Watanabe K, Mikami A, Tamada T, Yoshizawa H, Akazawa K, Tanaka T, Kitamura N, Nakata K
Organizer
ATS 2016
Place of Presentation
San Francisco(USA)
Year and Date
2016-05-17
Related Report
Int'l Joint Research
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