Developing a novel treatment and an order made therapy for gynecologic cancers targeting cell adhesion molecules

• Project/Area Number: 18390451
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Sapporo Medical University
• Principal Investigator: TSUYOSHI Saito Sapporo Medical University, 医学部, 教授 (90145566)
• Co-Investigator(Kenkyū-buntansha): TAKAHIRO Suzuki 札幌医科大学, 医学部, 講師 (60398328) ; TAKASHI Fujimoto 札幌医科大学, 医学部, 講師 (70398329)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥9,620,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥1,620,000); Fiscal Year 2008: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2007: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2006: ¥2,600,000 (Direct Cost: ¥2,600,000)
• Keywords: 子宮体癌 / 子宮内膜 / 遺伝子治療 / コネキシン / 卵巣癌 / ギャップ結合 / バイスタンダー効果 / ベイスタンダー効果

Research Abstract

初年度はin vitroにおいて子宮内膜癌細胞での細胞間コミュニケーションによるバイスタンダー効果を証明した。さらに性ステロイドホルモンやレチノイドなどを用いてより細胞間コミュニケーションを促進させることによりバイスタンダー効果が増強されるか検証を行った。
1. RL-952細胞におけるバイスタンダー効果の発現
HSV-tk遺伝子を導入したRL-952-HSV-tk細胞に対するGCVの添加実験では、20mMと2mMの濃度ではほとんどすべての細胞が96時間後には死滅し、200mMでは75%、20mMでは40%が96時間後に死滅した。以降の実験ではGCVの濃度は200・Mと20・Mで行った。
また、RL-952-HSV-tk細胞とRL-952-wildの混合培養にGCVを添加した実験では、フルシートのRL-952-wildにRL-952-HSV-tk細胞を100個、150個、200個、250個と増やしてゆくとそれに比例して死細胞数が増加した。
2. レチノイドがコネキシンの発現に与える影響
al trans-RAの添加実験では、レチノイドが100・Mの濃度でコネキシン26の発現が最も強く認められた。
3. in vitroでレチノイド投与がバイスタンダー効果に与える影響
in virtoでの実験を通じて生体内でのバイスタンダー効果の変動と最終的には新しい治療法の開発について研究を進めた。本年度は腹腔内腫瘍の形成と、レチノイド投与によってコネキシンの発現が変動する事を証明した。

Research Products

• [Journal Article] Chemotherapy (CT) with radiotherapy versus CT alone for FIGO Stage IIIc endometrial cancer (2009)
  • Author(s): Matsuura M, Suzuki T, Morishita M, Tanaka R, Ito E, Saito T.
  • Journal Title: Eur J Gynaecol Oncol 30 Pages: 40-4
  • Peer Reviewed
• [Journal Article] Spontaneous ovarian hyperstimulation syndrome and pituitary adenoma : incidental pregnancy triggers a catastrophic event (2009)
  • Author(s): Baba T, Endo T, Kitajima Y, Kamiya H, Moriwaka O, Saito T.
  • Journal Title: Fertil Steril [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Chemotherapy (CT) with radiotherapy versus CT alone for FIGO Stage IIIc endometrial cancer. . (2009)
  • Author(s): Saito T
  • Journal Title: Eur J Gynaecol Onco 30 Pages: 40-4
  • Peer Reviewed
• [Journal Article] Spontaneous ovarian hyperstimulation syndrome and pituitary adenoma : incidental pregnancy triggers a catastrophic event. (2009)
  • Author(s): Saito T
  • Journal Title: Fertil Steril. 25 Pages: 2798-803
  • Peer Reviewed
• [Journal Article] Analgesic efficacy of controlled-release oxycodone in patients with uterine or ovarian cancer (2008)
  • Author(s): Suzuki T, Morishita M, Ito E, Matsuura M, Tanaka R, Saito T.
  • Journal Title: Am J Ther 15 Pages: 31-5
  • Peer Reviewed
• [Journal Article] Analgesic efficacy of controlled-release oxycodone in patients with uterine or ovarian cancer. (2008)
  • Author(s): Saito T
  • Journal Title: Am J Ther. 15 Pages: 31-5
  • Peer Reviewed
• [Journal Article] Accuracy of magnetic resonance imaging for the evaluation of myometrial invasion in endometrial carcinoma (2007)
  • Author(s): Fujimoto T, Tamagawa M, Kimura M, Tanaka R, Umemura K, Ito E, Suzuki T, Hareyama M, Saito T.
  • Journal Title: Tumor Res 41 Pages: 71-6
  • NAID: 120001795087
  • Peer Reviewed
• [Journal Article] Advanced epithelial ovarian carcinoma during pregnancy (2007)
  • Author(s): Ishioka S, Hayashi T, Endo T, Baba T, Honma H, Saito T.
  • Journal Title: Int J Clin Oncol 12 Pages: 375-8
  • NAID: 10019800323
  • Peer Reviewed
• [Journal Article] Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women (2007)
  • Author(s): Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, Nakanishi T, Sasaki H, Saji F, Iwasaka T, Hatae M, Kodama S, Saito T, Terakawa N, Yaegashi N, Hiura M, Sakamoto A, Tsuda H, Fukunaga M, Kamura T.
  • Journal Title: J Clin Oncol 25 Pages: 2798-803
  • Peer Reviewed
• [Journal Article] Pregnancy-related complications after vaginal radical trachelectomy for early-stage invasive uterine cervical cancer (2007)
  • Author(s): Ishioka S, Endo T, Hayashi T, Baba T, Umemura K, Saito T.
  • Journal Title: Int J Clin Oncol 12 Pages: 350-5
  • NAID: 10019800235
  • Peer Reviewed
• [Journal Article] Polycystic ovary syndrome is associated with genetic polymorphism in the insulin signaling gene IRS-1 but not ENPP1 in a Japanese population (2007)
  • Author(s): Baba T, Endo T, Sata F, Honnma H, Kitajima Y, Hayashi T, Manase K, Kanaya M, Yamada H, Minakami H, Kishi R, Saito T.
  • Journal Title: Life Sci 81 Pages: 850-4
  • Peer Reviewed
• [Journal Article] Polycystic ovary syndrome is associated with genetic polymorphism in the insulin signaling gene IRS-1 but not ENPP1 in a Japanese population. (2007)
  • Author(s): Saito T
  • Journal Title: Life Sci 81 Pages: 850-4
  • Peer Reviewed
• [Journal Article] Accuracy of magnetic resonance imaging for the evaluation of myometrial invasion in endometrial carcinoma. (2007)
  • Author(s): Saito T
  • Journal Title: Tumor Res 41 Pages: 71-6
  • NAID: 120001795087
  • Peer Reviewed
• [Journal Article] Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. (2007)
  • Author(s): Saito T
  • Journal Title: J Clin Oncol 25 Pages: 2798-803
  • Peer Reviewed
• [Journal Article] Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines (2006)
  • Author(s): Terasawa K, Toyota M, Sagae S, Ogi K, Suzuki H, Sonoda T, Akino K., Maruyama R, Nishikawa N, Imai K, Shinomura Y, Saito T, Tokino T.
  • Journal Title: Br J Cancer 94 Pages: 914-921
  • Peer Reviewed
• [Journal Article] Elevation of Both Cyclooxygenase-2 and Prostaglandin E(2) Receptor EP3 Expressions in Rat Placenta after Uterine Artery Ischemia-Reperfusion (2006)
  • Author(s): Yamazaki K, Endo T, Kitajima Y, Manase K, Nagasawa K, Honnma H, Hayashi T, Kudo R, Saito T.
  • Journal Title: Placenta 27 Pages: 395-401
  • Peer Reviewed
• [Journal Article] Hyperstimulation and a Gonadotropin-Releasing Hormone Agonist Modulate Ovarian Vascular Permeability by Altering Expression of the Tight Junction Protein Claudin-5 (2006)
  • Author(s): Kitajima Y, Endo T, Nagasawa K, Manase K, Honnma H, Baba T, Hayashi T, Chiba H, Sawada N, Saito T.
  • Journal Title: Endocrinology 147 Pages: 694-9
  • Peer Reviewed
• [Journal Article] Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidyl- inositol and lipopolysaccharide (2006)
  • Author(s): Ohya M, Nishitani C, Sano H, Yamada C, Mitsuzawa H, Shimizu T, Saito T, Smith K, Crouch E, Kuroki Y.
  • Journal Title: Biochemistry 45 Pages: 8657-64
  • Peer Reviewed
• [Journal Article] Possible involvement of gap junctions in the barrier function of tight junctions of brain and lung endothelial cells (2006)
  • Author(s): Nagasawa K, Chiba H, Fujita H, Kojima T, Saito T, Endo T, Sawada N.
  • Journal Title: J Cell Physiol 208 Pages: 123-32
  • Peer Reviewed
• [Journal Article] Coordinated elevation of membrane type 1-matrix metalloproteinase and matrix metalloproteinase-2 expression in rat uterus during postpartum involution (2006)
  • Author(s): Manase K, Endo T, Chida M, Nagasawa K, Honnma H, Yamazaki K, Kitajima Y, Goto T, Kanaya M, Hayashi T, Mitaka T, Saito T.
  • Journal Title: Reprod Biol Endocrinol 2 Pages: 24-32
  • Peer Reviewed
• [Journal Article] Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metallo- proteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats (2006)
  • Author(s): Honnma H, Endo T, Henmi H, Nagasawa K, Baba T, Yamazaki K, Kitajima Y, Hayashi T, Manase K, Saito T.
  • Journal Title: Apoptosis 11 Pages: 1525-33
  • Peer Reviewed
• [Journal Article] Association between polycystic ovary syndrome and female-to-male transsexuality (2006)
  • Author(s): Baba T, Endo T, Honnma H, Kitajima Y, Hayashi T, Ikeda H, Masumori N, Kamiya H, Moriwaka O, Saito T.
  • Journal Title: Hum Reprod 22(4) Pages: 1011-6
  • Peer Reviewed
• [Journal Article] Proteomic analysis of mechanisms of hypoxia-induced apoptosis in trophoblastic cells (2006)
  • Author(s): Ishioka S, Ezaka Y, Umemura K, Hayashi T, Endo T, Saito T.
  • Journal Title: Int J Med Sci 4 Pages: 36-44
  • Peer Reviewed
• [Journal Article] Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide. (2006)
  • Author(s): Saito T
  • Journal Title: Biochemistry. 45 Pages: 8657-64
• [Journal Article] Coordinated elevation of membrane type 1-matrix metalloproteinase and matrix metalloproteinase-2 expression in rat uterus during postpartum involution. (2006)
  • Author(s): Saito T
  • Journal Title: Reprod Biol Endocrinol, 2 Pages: 4-32
• [Journal Article] Possible involvement of gap junctions in the barrier function of tight junctions of brain and lung endothelial cells. (2006)
  • Author(s): Saito T
  • Journal Title: J Cell Physiol. 208 Pages: 123-32
• [Journal Article] Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. (2006)
  • Author(s): Saito T
  • Journal Title: Apoptosis 11 Pages: 1525-33
• [Journal Article] Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines, (2006)
  • Author(s): Saito T
  • Journal Title: Br J Cancer 94 Pages: 914-921
• [Journal Article] Elevation of Both Cyclooxygenase-2 and Prostaglandin E(2) Receptor EP3 Expressions in Rat Placenta after Uterine Artery Ischemia-Reperfusion. (2006)
  • Author(s): Saito T
  • Journal Title: Placenta 27 Pages: 395-401
• [Presentation] 癌細胞におけるBAG3発現の意義 (2009)
  • Author(s): 両坂美和・岩崎雅宏・斉藤豪
  • Organizer: 第61回日本産科婦人科学会総会・学術講演会
  • Place of Presentation: 京都
• [Presentation] 卵巣癌におけるオステオポンチンの発現の検討 (2009)
  • Author(s): 松浦基樹・鈴木孝浩・伊東英樹・斉藤豪
  • Organizer: 第61回日本産科婦人科学会総会・学術講演会
  • Place of Presentation: 京都
• [Presentation] バイスタンダー効果を応用した遺伝子治療の研究 (2007)
  • Author(s): 鈴木孝浩、森下美幸、松浦基樹、藤本尚、斎藤豪
  • Organizer: 日本癌治療学会
  • Place of Presentation: 京都
• [Presentation] Bystander killing of uterine endometrial cancer cells by herpes simplex virus thymidine kinase is mediated by ganciclovir and retinoids (2006)
  • Author(s): Suzuki T, Morishita M, Matuura M, Tanaka R, Fujimoto T, Saito T.
  • Organizer: International Conference Physiology and Pathological Importance of GAP Junctions
  • Place of Presentation: 東京
  • Year and Date: 2006-10-22