2018 Fiscal Year Final Research Report

Mechanism of mTOR inhibitor-associated stomatitis

Research Project

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Project/Area Number	15K11309
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Surgical dentistry
Research Institution	Niigata University
Principal Investigator	Kitamura Nobutaka 新潟大学, 医歯学総合病院, 特任教授 (90224972)
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)
Research Collaborator	IZUMI Kenzi ITO Yuko YAMAMOTO Youka OHHASHI Riuko HUJIMOTO Yoko WATANABE Mari
Project Period (FY)	2015-04-01 – 2019-03-31
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
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.
Free Research Field	口腔外科学、生物統計学
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。