Strategy for the development of new therapy for uterine leiomyoma based on the analysis of sex steroidal action in leiomyoma growth

• Project/Area Number: 18390449
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kobe University
• Principal Investigator: OHARA Noriyuki (2008) Kobe University, 医学部附属病院, 准教授 (70214210); 丸尾 猛 (2006-2007) Kobe University, 大学院・医学系研究科, 教授 (60135811)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Shigeki 神戸大学, 医学部附属病院, 講師 (70294212) ; NAKABAYASHI Koji 神戸大学, 医学系研究科, 助教 (80362789) ; MATSUO Hiroya 神戸大学, 保健学研究科, 教授 (60229432) ; 小原 範之 神戸大学, 医学部附属病院, 准教授 (70214210)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,410,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥2,010,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2007: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2006: ¥8,700,000 (Direct Cost: ¥8,700,000)
• Keywords: 子宮筋腫 / プロゲステロン受容体モデュレーター / アポトーシス / 細胞外基質蛋白 / コラーゲン / 増殖 / SPRM / CDB-2914 / J867 / 筋腫細胞 / Progesterone receptor

Research Abstract

我々は新しい子宮筋腫治療薬として期待されているプロゲステロン受容体モデュレーター(selective progesterone receptor modulator : SPRM)が子宮筋腫細胞において細胞増殖を抑制し、同時にアポトーシスを誘導することを世界に先駆けて明らかにした。今回の研究でSPRMは小胞体ストレス誘導に続いてアポトーシス関連蛋白発現に影響を及ぼしていることを示した。さらに、SPRMが子宮筋腫細胞での細胞外基質蛋白関連蛋白発現を修飾し、コラーゲン生成を抑制させることを初めて明らかにした。SPRMは子宮筋腫の細胞死を誘導し、またコラーゲン合成を抑制することで子宮筋腫発育を抑制している可能性が推測された。

Research Products

• [Journal Article] プロゲステロンの実用化の現状 (2008)
  • Author(s): 小原範之
  • Journal Title: 日本医事新報 No.4386 Pages: 94-95
  • Peer Reviewed
• [Journal Article] Regulatory mechanism of Bcl-2 in uterine leiomyomas (2008)
  • Author(s): Ohara N
  • Journal Title: Clin Exp Obstet Gynecol 35 Pages: 1240-241
  • Peer Reviewed
• [Journal Article] Action of progesterone receptor modulators on uterine leiomyomas (2008)
  • Author(s): Ohara N
  • Journal Title: Clin Exp Obstet Gynecol 35 Pages: 165-166
  • Peer Reviewed
• [Journal Article] Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer (2008)
  • Author(s): Morikawa A, Ohara N, Xu Q, Nakabayashi K, DeManno DA, Chwalisz K, Yoshida S, Maruo T
  • Journal Title: Hum Reprod 23 Pages: 944-951
  • Peer Reviewed
• [Journal Article] Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells (2008)
  • Author(s): Xu Q, Ohara N, Liu J, Amano M, Sitruk-Ware R, Yoshida S, Maruo T
  • Journal Title: Mol Hum Reprod 14 Pages: 181-191
  • Peer Reviewed
• [Journal Article] Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellularmatrix metalloproteinase inducer (2008)
  • Author(s): Morikawa H, Ohara N, Xu Q, Nakabayashi K, DeManno DA, Chwalisz K, Yoshida s, Maruo T
  • Journal Title: Hum Reprod 23 Pages: 944-951
  • Peer Reviewed
• [Journal Article] Effects of progesterone receptor modulator CDB-2914 0n the expression of extracellularmatrix proteins in cultured human uterine leiomyoma cells (2008)
  • Author(s): Xu Q, Ohara N, Liu J, Amano M, Sitruk-Ware R, Yoshida s, Maruo T
  • Journal Title: Mol Hum Reprod 14 Pages: 181-191
  • Peer Reviewed
• [Journal Article] Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells (2007)
  • Author(s): Xu Q, Ohara N, Liu J, Nakabayashi K, DeManno D, Chwalisz K, Yoshida S, Maruo T
  • Journal Title: Am J Physiol Endocrinol Metab 293
  • Peer Reviewed
• [Journal Article] Comparative effects of SPRM asoprisnil(J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells (2007)
  • Author(s): Ohara N, Morikawa A, Chen W, Wang J, DeManno DA, Chwalisz K, Maruo T
  • Journal Title: Reprod Sci 14 Pages: 20-27
  • Peer Reviewed
• [Journal Article] Effects of levonorgestrel-releasing IUS and progesterone receptor modulator PRM CDB-2914 on uterine leiomyomas (2007)
  • Author(s): Maruo T, Ohara N, Matsuo H, Xu Q, Chen W, Sitruk-Ware R, Johansson EDB
  • Journal Title: Contraception 75
  • Peer Reviewed
• [Journal Article] A novel selective progesterone receptor modulator Asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells (2006)
  • Author(s): Chen W, Ohara N, Wnag J, Xu Q, Liu J, Morikawa A, Sasaki H, Yoshida S, DeManno DA, Chwalisz K, Maruo T
  • Journal Title: J Clin Endocrinol Metab 91 Pages: 1296-1304
• [Journal Article] A novel selective progesterone receptor modulator Asoprisnil (J867) down-regulates the expression of EGF, IGF-I, TGF β 3, and their receptors in cultured uterine leiomyoma cells (2006)
  • Author(s): Wang J, Ohara N, Wang Z, Chen W, Morikawa A, Sasaki II, DeManno DA, Chwalisz K, Maruo T
  • Journal Title: Hum Reprod 21 Pages: 1869-1877
• [Journal Article] Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells (2006)
  • Author(s): Xu Q, Ohara N, Chen W, Liu J, Sasaki H, Morikawa A, Sitruk-Ware R, Johansson ED, Maruo T
  • Journal Title: Hum Reprod 21 Pages: 2408-2416
• [Journal Article] A putative role of versican in uterine leiomyomas
  • Author(s): Ohara N
  • Journal Title: Clin Exp Obstet Gynecol (in press)
  • Peer Reviewed
• [Journal Article] Sex steroidal modulation of collagen metabolism in uterine leiomyomas
  • Author(s): Ohara N
  • Journal Title: Clin Exp Obstet Gynecol (in press)
  • Peer Reviewed
• [Journal Article] Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer
  • Author(s): Morikawa H, Ohara N, Xu Q, Nakabayashi K, DeManno DA, Chwalisz K, Yoshida S, Maruo T
  • Journal Title: Hum Reprod (in press)
  • Peer Reviewed
• [Journal Article] Effects of progesterone receptor modulator CDB-2914 on the expression of extracellular matrix proteins in cultured human uterine leiomyoma cells
  • Author(s): Xu Q, Ohara N, Liu J, Amano M, Sitruk-Ware R, Yoshida S, Maruo T
  • Journal Title: Mol Hum Reprod (in press)
  • Peer Reviewed
• [Presentation] Attack on uterine fibroids by progesterone receptor modulator in a cell-type specific manner (2008)
  • Author(s): Maruo T
  • Organizer: International Workshop on Uterine Fibroids
  • Place of Presentation: Germany
• [Presentation] Attack on uterine fibroids by progesterone receptor modulator in acell-type specific manner (2008)
  • Author(s): Maruo T, et al
  • Organizer: International Workshop on Uterine Fibroids
  • Place of Presentation: Berlin, Germany
• [Presentation] Progesterone and progesterone receptor modulator in uterine leiomyoma growth. The Oxford-Kobe Biomedical Seminar (2007)
  • Author(s): Maruo T, Matsuo H, Ohara N, Samoto T, Nakago S, Xu Q, Chen W, Wang J
  • Organizer: International Symposium on Translational Research in Uterine Biology
  • Place of Presentation: Kobe, Japan
• [Presentation] Effects of CDB-2914 on ECM expression in cultured leiomyoma cells (2007)
  • Author(s): Maruo T
  • Organizer: The 91th International Committee Meeting of the Population Council
  • Place of Presentation: New York, USA
• [Presentation] Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured uterine leiomyoma cells (2007)
  • Author(s): Xu Q, Ohara N, Liu J, Sasaki H, Morikawa A, Yoshida S, DeManno D, Chwalisz K, Maruo T
  • Organizer: The 20th Asian and Oceanic Congress of Obstetrics and Gynecology
  • Place of Presentation: Tokyo, Japan
• [Presentation] Progesterone and progesterone receptor modulator in uterine leiomyoma growth : their implication in reproductive health (2007)
  • Author(s): Maruo T, Matsuo H, Samoto T, Nakago S, Xu Q, Chen W, Wang J, Ohara N
  • Organizer: The 12th Annual Conference of the Egyptian Fertility and Sterility Society
  • Place of Presentation: Cairo, Egypt
• [Presentation] Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells (2007)
  • Author(s): Xu Q, Ohara N, Liu J, Morikawa A, Sasaki H, Maruo T
  • Organizer: 第59回日本産科婦人科学会
  • Place of Presentation: 京都
• [Presentation] 子宮筋腫における選択的プロゲステロン受容体モデュレーターJ867のコラーゲン関連タンパク発現への影響の検討 (2007)
  • Author(s): 森川哲、小原範之、中林幸士、丸尾猛
  • Organizer: 第59回日本産科婦人科学会
  • Place of Presentation: 京都
• [Presentation] プロゲステロン受容体モデュレーターならびにGnRH antagonistによるヒト子宮筋腫細胞発育制御機構の解析 (2007)
  • Author(s): 小原範之
  • Organizer: 第59回日本産科婦人科学会
  • Place of Presentation: 京都
• [Presentation] Progesterone and progesterone receptor modulator in uterine leiomyoma growth: their implication in reproductive health (2007)
  • Author(s): Maruo T, Matsuo H, Samoto T, Nakago S, Xu Q, Chen W, Wang J, Ohara N
  • Organizer: The 12th Annual Conference of Egyptian Fertility and Sterility Society
  • Place of Presentation: Cairo, Egypt,
• [Presentation] Progesterone and selective progesterone receptor modulator in uterine leiomyoma growth.International Seminar in Reproductive Endocrinology (2006)
  • Author(s): Maruo T, Matsuo H, Xu Q, Chen W, Wang J, Ohara N
  • Place of Presentation: Siena, Italy
  • Year and Date: 2006-02-28
• [Presentation] Comparative effects of SPRM asoprisnil(J867)on the proliferation, apoptosis and the expression of growth factors and ECM in cultured uterine leiomyoma cells and normal myometrial cells (2006)
  • Author(s): Maruo T, Ohara N, Morikawa A, Chen W, Wang J, DeManno D, Chwalisz K
  • Organizer: The 8th International Conference on the Extracellular Matrix of the Female Reproductive Tract
  • Place of Presentation: Maui, Hawaii, USA
• [Presentation] In vitro effects of progesterone and progesterone receptor modulator on uterine leiomyoma growth (2006)
  • Author(s): Maruo T, Ohara N, Matsuo H, Nakago S, Yamada T, Chen W, Xu Q, Wang J, Sitruk-Ware R, Johansson EDB
  • Organizer: The XVIII FIGO World Congress of Gynecology and Obstetrics
  • Place of Presentation: Kuala Lumpur, Malaysia
• [Presentation] Progesterone receptor modulator(CDB-2914) induces apoptosis and inhibits proliferation and VEGF expression in cultured uterine leiomyoma cells but not in cultured normal myometrial cells (2006)
  • Author(s): Maruo T, Ohara N, Xu Q, Chen W, Sitruk-Ware R, Johansson EDB
  • Organizer: The XVIII FIGO World Congress of Gynecology and Obstetrics
  • Place of Presentation: Kuala Lumpur, Malaysia
• [Presentation] Comparative effects of progesterone and PRM CDB-2914 on cultured uterine leiomyoma cells and myometrial cells (2006)
  • Author(s): Maruo T, Matsuo H, Ohara N, Xu Q, Chen W, Sitruk-Ware R, Johansson EDB
  • Organizer: The 89th International Committee Meeting of the Population Council
  • Place of Presentation: New York, USA
• [Presentation] Effects of CDB-2914 on PR-A and PR-B in leiomyoma and normal myometrium (2006)
  • Author(s): Maruo T
  • Organizer: The 89th International Committee Meeting of the Population Council
  • Place of Presentation: New York, USA
• [Presentation] Progesterone and selective progesterone receptor modulator in uterine leiomyoma growth (2006)
  • Author(s): Maruo T, Matsuo H, Samoto T, Shimomura Y, Kurachi O, Nakago S, Yamada T, Xu Q, Chen W, Wang J, Ohara N
  • Organizer: The 92th Annual Congress of the Korean Society of Obstetrics and Gynecology
  • Place of Presentation: Seoul, Korea
• [Presentation] プロゲステロン受容体モデュレーターCDB-2914は培養子宮筋腫細胞におけるVEGF, adrenomedullinとその受容体発現を抑制する (2006)
  • Author(s): 徐沁、小原範之、佐々木紘子、陳衛、丸尾猛
  • Organizer: 第58回日本産科婦人科学会
  • Place of Presentation: 横浜
• [Presentation] 選択的プロゲステロン受容体モデュレーターJ867は組織選択的に培養子宮筋腫細胞の増殖を阻害し、アポトーシスを誘導する (2006)
  • Author(s): 森川哲、小原範之、陳衛、王佳茵、丸尾猛
  • Organizer: 第58回日本産科婦人科学会
  • Place of Presentation: 横浜
• [Presentation] SPRM asoprisnil(J867)inhibits the proliferation and induces apoptosis in cultured uterine leiomyoma cells but not in cultured normal myometrial cells (2006)
  • Author(s): Maruo T, Ohara N, Chen W, Wang J, DeManno D, Chwalisz K
  • Organizer: The 12th World Congress of Gynecological Endocrinology
  • Place of Presentation: Florence, Italy
• [Book] Translational research in uterine biology (2008)
  • Author(s): Ohara N, Xu Q, Matsuo H, Maruo T
  • Publisher: Elsevier, Amsterdam, Progesterone and progesterone receptor modulator in uterine leiomyoma growth
• [Book] 子宮筋腫とSPRM : 子宮筋腫治療の新戦略. Annual Review 糖尿病・代謝・内分泌 (2008)
  • Author(s): 小原範之、丸尾猛
  • Publisher: 中外医学社
• [Book] 子宮筋腫研究の最近の話題と今後の展望. 子宮筋腫の臨床 (2008)
  • Author(s): 小原範之、丸尾猛
  • Publisher: メジカルビュー社
• [Book] Progesterone and progesterone receptor modulator in uterine leiomyomagrowth (2008)
  • Author(s): Ohara N, et al
  • Publisher: Elsevier, Amsterdam
• [Book] Translational research in uterine biology (2008)
  • Author(s): Ohara N, Xu Q, Matsuo H, Maruo T
  • Publisher: Elsevier(In press)