Development of anti-cancer therapy combined with cyclooxygenase-2 inhibitors

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590639
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TSUJII Masahiko Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (40303937)
• Co-Investigator(Kenkyū-buntansha): KAWANO Sunao Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (60133138) ; TSUJI Shingo Osaka University, Graduate School of Medicine, Assistant professor, 医学系研究科, 講師 (40301262)
• Project Period (FY): 2005 – 2006
• Keywords: cyclooxygenase / colon cancer / tumon angiogenesis / chemotherapy / interferon-γ

Research Abstract

Background ＆ Aims : Cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colorectal cancers. For treatment of advanced cancers, combination of COX-2 inhibitors and chemotherapy has been attempted, but the results are still controversial. In the present study, the effects of the COX-2 inhibitor celecoxib on the anticancer potential of chemotherapy, and its mechanisms of action were investigated in point of the angiogenesis and the immune response using an advanced cancer model in mice.
Methods : BALB/c mice or BALB/c IFN-γ null mice were inoculated with colon 26 cells. After the allograft grew up to 5mm in diameter, the animals received celecoxib (3mg/kg), 5FU (20mg/kg), or a combination of 5FU and celecoxib (5FU/celecoxib). After 21-days of the treatment, tumors were harvested and used for analyzing angiogenesis (expression of CD31) or leukocyte infiltration (CD45 expression) by immunohistochemistry and for measuring VEGF, IFN-γ concentration by ELISA. The fr equency of infiltrating immune cells in the tumors was also analyzed by flow cytometric analyses.
Result s: 5FU/celecoxib significantly inhibited the tumor growth and the tumor vessel density compared with the other groups. Celecoxib, 5FU or 5FU/celecoxib significantly suppressed the VEGF content in tumor tissues. 5FU/celecoxib also enhanced IFN-γ levels in tumor tissue, which could be involved in the potent antitumor effects of 5FU/celecoxib. This hypothesis was proven, because in IFN-γ null mice, the inhibitory effects of 5FU/celecoxib on angiogenesis and tumor growth were significantly impaired compared with that in wild type mice. 5FU decreased leukocyte infiltration and increased CD4+CD25^<high> T cell frequency, but the addition of celecoxib reversed these 5FU treatment related effects. 5FU and 5FU/celecoxib increased frequency of matured dendritic cells in the tumors compared with control.
Conclusion : These results suggest that celecoxib enhances the antitumor effect of 5FU against an advanced colon cancer model by suppressing angiogenesis and enhancing the immune response against the tumor. In addition to VEGF, IFN-γ has pivotal roles in tumor suppression induced by a COX-2 inhibitor.

Research Products

• [Journal Article] Synergistic antitumor effects of celecoxib with 5-fluorouracil depend on IFN-γ (2007)
  • Author(s): Irie T, Tsujii M, Tsuji S, Yoshio T, Ishii S, Shinzaki S, Egawa S, Kakiuchi Y, et al.
  • Journal Title: International Journal of Cancer (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] East Asian-type Helicobacter pylori cytotoxin-associated gene A protein has a more significant effect on growth of rat gastric mucosal cells than the Western type. (2007)
  • Author(s): Fu HY, Asahi K, Hayashi Y, Eguchi H, Murata H, Tsujii M, Tsuji S, Azuma T, Kawano S
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 355-362
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] East Asian-type Helicobacter pylori cytotoxin-associated gene A protein has a more significant effect on growth of rat gastric mucosal cells than the Western type. (2007)
  • Author(s): Fu HY, Asahi K, Hayashi Y, Eguchi H, Murata H, Tsujii M, Tsuji S, Azuma T, Kawano S.
  • Journal Title: J Gastroenterol Hepatol. 22 Pages: 355-362
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori eradication to prevent gastric cancer : underlying molecular and cellular mechanisms. (2006)
  • Author(s): Tsuji S, Tsujii M, Murata H, Nishida T, Komori M, Yasumaru M, et al.
  • Journal Title: World J Gastroenterol. 12 Pages: 167-180
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis (2006)
  • Author(s): Nishida T, Tsuji S, Tsujii M, Arimitsu S, Haruna Y, Imano E, Suzuki M, Kanda T. et al.
  • Journal Title: Am J Gastroenterol. 101 Pages: 70-75
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibrobplasts and stimulates production of stroma-derived factors. (2006)
  • Author(s): Nishida T, Tsuji S, Kimura A, Tsujii M, Ishii S, Yoshio T, Shinzaki S, Egawa S, et al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. 290 Pages: G1041-1050
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis (2006)
  • Author(s): Nishida T, Tsuji S, Tsujii M, Arimitsu S, Haruna Y, Imano E, Suzuki M, Kanda T, et al.
  • Journal Title: Am J Gastroenterol. 101 Pages: 70-75
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors (2006)
  • Author(s): Nishida T, Tsuji S, Kimura A, Tsujii M, Ishii S, Yoshio T, Shinzaki S, Egawa S, et al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. 290 Pages: G1041-1050
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Recent Advances in Gastrointestinal Carcinogenesis (2006)
  • Author(s): Tsujii M, Tsuji S, Irie T, Kakiuchi Y, Yasumaru M, Kawano S, Hayashi N.
  • Journal Title: Recent Advances in Gastrointestinal Carcinogenesis. Pages: 247
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Combination of enprostil and cimetidine is more effective than cimetidine alone in treating gastric ulcer : prospective multicenter randomized controlled trial. (2005)
  • Author(s): Murata H, Kawano S, Tsuji S, Tsujii M, Hori M, Kamada T, Matsuzawa Y, Katsu K, Inoue K, Kobayashi K, Mitsufuji S, Bamba T, Kawasaki H, Kajiyama G, Umegaki E, Inoue M, Saito I
  • Journal Title: Hepatogastroenterology 52 Pages: 1925-1929
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] (2E,6Z,10E)-7-hydxoxymethyl-3,11,15-trimethyl-2,6,10,14-hex adecatetraen-1-ol (Plaunotol) increases cyclooxygenase-2 expression via nuclear factor kappaB and cyclic AMP response element in rat gastric epithelial cells. (2005)
  • Author(s): Fu H, Yabe Y, Asahi K, Hayashi Y, Murata H, Eguchi H, Tsujii M, Tsuji S, kawano S
  • Journal Title: Eur J Pharmacol. 7;524 Pages: 38-43
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gastro-protective agent rebamipide induces cyclooxygenease-2 (COX-2) in gastric epithelial cells. (2005)
  • Author(s): Murata H, Yabe Y, Tsuji S, Tsujii M, Fu HY, Asahi K, Eguchi H, Kawano S, Hayashi N
  • Journal Title: Dig Dis Sci. 50 Pages: S70-75
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Efficiency of bone marrow-derived cells in regeneration of the stomach after induction of ethanol-induced ulcers in rats. (2005)
  • Author(s): Komori M, Tsuji S, Tsujii M, Murata H, Iijma H, Yasumaru M, Nishida T, Irie T, Kawano S, Hori M
  • Journal Title: J Gastroenterol. 40 Pages: 591-599
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of bone marrow-derived cells in healing of experimental colitis in rats. (2005)
  • Author(s): Komori M, Tsuji S, Tsujii M, Murata H, Iijima H, Yasumaru M, Nishida T, Irie T, Kawano, S. Hori M
  • Journal Title: Wound Repair Regen. 13 Pages: 109-118
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Juvenile hepatocellular carcinoma with congestive liver cirrhosis. (2005)
  • Author(s): Izumi Y, Hiramatsu N, Itose I, Inoue T, Sasagawa A, Egawa S, Nishida T, Kakiuchi Y, Toyama T, Nakanishi F, Ohkawa K, Mochizuki K, Kanto T, Tsujii M, Takehara T, Tsuji S, Kato M, Kasahara A, Hayashi N.
  • Journal Title: Gastroenterol. 40 Pages: 204-208
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Combination of enprostil and cimetidine is more effective than cimetidine alone in treating gastric ulcer : prospective multicenter randomized controlled trial. (2005)
  • Author(s): Murata H, Kawano S, Tsuji S, Tsujii M, Hori M, Kamada T, Matsuzawa Y, Katsu K, Inoue K, Kobayashi K, Mitsufuji S, Bamba T, Kawasaki H, Kajiyama G, Umegaki E, Inoue M, Saito I.
  • Journal Title: Hepatogastroenterology. 52 Pages: 1925-1929
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] (2E,6Z,10E)-7-hydroxymethy1-3, 11,15-trimethy1-2,6, 10,14-hexadecatetraen-1-ol (Plaunotol) increases cyclooxygenase-2 expression via nuclear factor kappaB and cyclic AMP response element in rat gastric epithelial cells. (2005)
  • Author(s): Fu H, Yabe Y, Asahi K, Hayashi Y, Murata H, Eguchi H, Tsujii M, Tsuji S, Kawano S.
  • Journal Title: Eur J Pharmacol. 7;524 Pages: 38-43
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gastro-protective agent rebamipide induces cyclooxygenease-2 (COX-2) in gastric epithelial cells. (2005)
  • Author(s): Murata H, Yabe Y, Tsuji S, Tsujii M, Fu HY, Asahi K, Eguchi H, Kawano S. Hayashi N.
  • Journal Title: Dig Dis Sci. 50(Suppl 1) Pages: S70-75
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Efficiency of bone marrow-derived cells in regeneration of the stomach after induction of ethanol-induced ulcers in rats. (2005)
  • Author(s): Komori M, Tsuji S, Tsujii M, Murata H, Iijima H, Yasumaru M, Nishida T, Irie T, Kawano S, Hori M.
  • Journal Title: J Gastroenterol. 40 Pages: 591-599
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Juvenile hepatocellular carcinoma with congestive liver cirrhosis. (2005)
  • Author(s): Izumi Y, Hiramatsu N, Itose I, Inoue T, Sasagawa A, Egawa S, Nishida T, Kakiuchi Y, Toyama T, Nakanishi F, Ohkawa K, Mochizuki K, Kanto T, Tsujii M, Takehara T, Tsuji S, Kato M, Kasahara A, Hayashi N.
  • Journal Title: J Gastroenterol. 40 Pages: 204-208
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of bone marrow-derived cells in healing of experimental colitis in rats. (2005)
  • Author(s): Komori M, Tsuji S, Tsujii M, Murata H, Iijima H, Yasumaru M, Nishida T, Irie T, Kawano S, Hori M.
  • Journal Title: Wound Repair Regen. 13 Pages: 109-118
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Geranylgeranylacetone Induces Cyclooxygenase-2 Expression in Cultured Rat Gastric Epithelial Cells Through NF-kappaB.
  • 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. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synergistic antitumor effects of celecoxib with 5-fluorouracil depend on IFN-γ.
  • Author(s): Irie T, Tsujii M, Tsuji S, Yoshio T, Ishii S, Shinzaki S, Egawa S, Kakiuchi Y, et al.
  • Journal Title: International Journal of Cancer (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Geranylgeranylacetone Induces Cyclooxygenase-2 Expression in Cultured Rat Gastric Epithelial Cells Through NF-kappaB.
  • 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. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Recent Advances in Gastrointestinal Carcinogenesis (2006)
  • Author(s): Tsujii M, Tsuji S, Irie T, Kakiuchi Y, Yasumaru M, Kawano S, Hayashi N.
  • Total Pages: 247
  • Publisher: Transworld Research Network
  • Description: 「研究成果報告書概要(和文)」より