腫瘍免疫・血管新生からみた大腸癌化学療法の抗腫瘍活性増強に関わる標的分子の探索

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19590722
• Research Institution: Osaka University
• Principal Investigator: 辻井 正彦 Osaka University, 医学系研究科, 講師 (40303937)
• Co-Investigator(Kenkyū-buntansha): 辻 晋吾 大阪大学, 医学系研究科, 講師 (40301262) ; 飯島 英樹 大阪大学, 医学系研究科, 助教 (90444520)
• Keywords: COX阻害剤 / 血管新生 / インターフェロン / 悪疫質 / VEGF

Research Abstract

疫学的検討から、NSAIDsの大腸癌の予防薬としての有効性が示唆されているが、我々は、その標的分子cyclooxygenase(COX)のうちの誘導型のCOX-2が大腸腫瘍で高発現しており、腫瘍細胞増殖、抗アポトーシス、腫瘍血管新生、腫瘍の浸潤転移、腫瘍免疫抑制など癌の発生進展において重要な働きをしていることを明らかにし、COX阻害剤の癌予防薬としての有用性を報告してきた。本検討では、癌治療におけるCOX-2阻害剤の有効性を明らかにするため、マウスの皮下移植腫瘍に対し、5mm以上の大きさになってから、治療薬の投与を開始するモデルを用いた。COX-2阻害剤と5FUを併用した場合、それぞれ単独で使用した場合に比し、相乗的に抗腫瘍効果の増強が認められた。そのメカニズムとしては、COX-2阻害剤と5FUは両方ともVEGF産生抑制効果を示し、併用により相加的にVEGF産生抑制効果が得られること、5FUによりIFN-γ産生が抑制されるのに対し、COX阻害剤を併用することによりIFN-γ産生が誘導されること、更にIFN-γノックアウトマウスを用いた検討からIFN-γが腫瘍血管新生抑制作用を呈することが明らかとなった。更にCOX阻害剤は担がん動物や5FU投与に伴う悪疫質を改善する効果を有していることが明らかとなった。但し、COX阻害剤を併用した場合、腫瘍細胞内で5FU分解酵素が誘導され、5FUのDNA・RNA合成阻害効果はCOX阻害剤存在下では減弱することが明らかとなり、DPD阻害剤などの併用により、COX阻害剤による5FUの抗腫瘍効果の減弱が回避されることが示唆された。

Research Products

• [Journal Article] Topical Transplantation of Mesenchymal Stem Cells Accelerates Gastric Ulcer Healing in Rats. (2008)
  • Author(s): Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, Kawano S.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Pages: Epud ahead
  • Peer Reviewed
• [Journal Article] IgG Oligosaccharide Alterations Are a Novel Diagnostic Marker for Disease Activity and the Clinical Course of Inflammatory Bowel Disease. (2008)
  • Author(s): Shinzaki S, Iijima H, Nakagawa T, Egawa S, Nakajima S, Ishii S, Irie T, Kakiuchi Y, Nishida T, Yasumaru M, Kanto T, Tsujii M, Tsuji S, Mizushima T, Yoshihara H, Kondo A, Miyoshi E, Hayashi N.
  • Journal Title: Am J Gastroenterol. Pages: Epud ahead
  • Peer Reviewed
• [Journal Article] Helicobacter pylori infection affects Toll-like receptor 4 expression in human gastric mucosa. (2007)
  • Author(s): Asahi K, Fu HY, Hayashi Y, Eguchi H, Murata H, Tsujii M, Tsuji S, Tanimura H, Kawano S.
  • Journal Title: Hepatogastroenterology. 54 Pages: 1941-1944
  • Peer Reviewed
• [Journal Article] Helicobacter pylori infection induces candidate stem cell marker musashi-1 in the human gastric epithelium. (2007)
  • Author(s): Murata H, Tsuji S, Tsujii M, Nakamura T, Fu HY, Eguchi H, Asahi K, Okano H, Kawano S, Hayashi N.
  • Journal Title: Dig Dis Sci. 53 Pages: 363-369
  • Peer Reviewed
• [Journal Article] Synergistic antitumor effects of celecoxib with 5-fluorouracil depend on IFN-gamma. (2007)
  • Author(s): Irie T, Tsujii M, Tsuji S, Yoshio T, Ishii S, Shinzaki S, Egawa S, Kakiuchi Y, Nishida T, Yasumaru M, Iijima H, Murata H, Takehara T, Kawano S, Hayashi N.
  • Journal Title: Int J Cancer. 121 Pages: 878-883
  • Peer Reviewed
• [Journal Article] Geranylgeranylacetone induces cyclooxygenase-2 expression in cultured rat gastric epithelial cells through NF-kappaB. (2007)
  • Author(s): Nishida T, Yabe Y, Fu HY, Hayashi Y, Asahi K, Eguchi H, Tsuji S, Tsujii M, Hayashi N, Kawano S.
  • Journal Title: Dig Dis Sci. 52 Pages: 1890-1896
  • Peer Reviewed
• [Journal Article] Caldesmon suppresses cancer cell invasion by regulating podosome/invadopodium formation. (2007)
  • Author(s): Yoshio T, Morita T, Kimura Y, Tsujii M, Hayashi N, Sobue K.
  • Journal Title: FEBS Lett. 581 Pages: 3777-3782
  • Peer Reviewed
• [Journal Article] The transdifferentiation of bone-marrow-derived cells in colonic mucosal regeneration after dextran-sulfate-sodium-induced colitis in mice. (2007)
  • Author(s): Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Nakamura T, Eguchi H, Kawano S.
  • Journal Title: Pharmacology. 80 Pages: 193-199
  • Peer Reviewed
• [Journal Article] Possibilities of prevention of colonic neoplasms (2007)
  • Author(s): Tsujii M
  • Journal Title: Nippon Naika Gakkai Zasshi. 96 Pages: 295-304
• [Presentation] DNA damage enhanced DNA methyltransferase activity via COX-2 and Erk activation, leading to aberrant hypermethylation (2007)
  • Author(s): M. Tsujii, S. Tsuji, T. Kanto, T. Takehara, N. Hayashi
  • Organizer: 日本がん学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] Endoscopic Full-Thickness Resection (EFTR), a New Technique for Treatment of Gastric Malignancy. (2007)
  • Author(s): M Yasumaru, S Tsuji, M Tsujii, S Tsutsui, T Yoshio, S Nakajima, S Ishii, S Shinzaki, S Egawa, T Irie, T Nishida, Y Kakiuchi, H Iijima, S Kawano, N Hayashi
  • Organizer: Digestive Disease Week and 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington, DC
  • Year and Date: 2007-05-22
• [Presentation] Expression of Grail, An E3 Ubiquitin-Ligase for Induction of T Cell Anergy, in Cd4+ T Cells of Patients with Ulcerative Colitis. (2007)
  • Author(s): S Egawa, H Iijima, S Shinzaki, S Nakajima, J Kondo, S Ishii, T Yoshio, T Irie, Y Kakiuchi, T Nishida, M Yasumaru, M Tsujii, S Tsuji, N Hayashi.
  • Organizer: Digestive Disease Week and 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington, DC
  • Year and Date: 2007-05-21
• [Presentation] Interferon-Gamma-Dependent Tumor-Suppressive Mechanisms of a COX-2 Inhibitor in Combination with 5-Fluorouracil. (2007)
  • Author(s): T Irie, M Tsujii, S Tsuji, S, T Yoshio, S Ishii, S Shinzaki, S Egawa, Y Kakiuchi, T Nishida, M Yasumaru, H Iijima, H Murata, T Takehara, S Kawano, N Hayashi
  • Organizer: Digestive Disease Week and 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington, DC
  • Year and Date: 2007-05-21
• [Presentation] Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Ameliorated 2,4,6-Trinitrobenzene sulfonic Acid (TNBS)-Induced Colitis in Rats. (2007)
  • Author(s): Y Hayashi, S Tsuji, M Tsujii, T Nishida, S Ishii, M Komori, T Irie, H Iijima, H Eguchi, N Hayashi, S Kawano.
  • Organizer: Digestive Disease Week and 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington, DC
  • Year and Date: 2007-05-20
• [Presentation] Cyclooxygenase-2 Regulates Toll-like Receptor (TLR)2 Expression and Tlr2-Mediated Chemokine Production in Intestinal Epithelial Cells. (2007)
  • Author(s): S Shinzaki, H Iijima, S Egawa, S Nakajima, S Ishii, T Yoshio, T Irie, Y Kakiuchi, T Nishida, M Yasumaru, T Kanto, M Tsujii, S Tsuji, N Hayashi
  • Organizer: Digestive Disease Week and 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington, DC
  • Year and Date: 2007-05-20
• [Presentation] DNA Damage-Related Hypomethylation Induced Not Senescence Nor Apoptosis, But Aberrant Hypermethylation in CpG Island Methylator Phenotype-High Colon Cancer Cells Via Aberrant Erk/Akt Activation and Enhanced DNA Methyltransferase Activity. (2007)
  • Author(s): M Tsujii, S Tsuji, S Tsutsui, H Iijima, M Yasumaru, T Nishida, T Irie, S Egawa, S Shinzaki, S Ishii, S Nakajima, T Yoshio, J Kondo, H Eguchi, S Kawano, N Hayashi.
  • Organizer: Digestive Disease Week and 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington, DC
  • Year and Date: 2007-05-20
• [Presentation] 糖鎖解析に基づく炎症性腸疾患の新たな血清マーカー (2007)
  • Author(s): 新崎信一郎、飯島英樹、中島佐知子、柄川悟志、考藤達哉、三善英知、辻井正彦、辻 晋吾、吉原治正、林 紀夫
  • Organizer: 第93回日本消化器病学会総会
  • Place of Presentation: 青森
  • Year and Date: 2007-04-20
• [Presentation] 潰瘍性大腸炎患者におけるT細胞不応答性の検討 (2007)
  • Author(s): 柄川悟志、飯島英樹、新崎信一郎、中島佐知子、石井修二、由雄敏之、入江孝延、垣内佳美、安丸正一、考藤達哉、辻井正彦、辻 晋吾、吉原治正、林 紀夫
  • Organizer: 第93回日本消化器病学会総会
  • Place of Presentation: 青森
  • Year and Date: 2007-04-20