| Project/Area Number |
17590639
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
TSUJII Masahiko Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (40303937)
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| 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)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | cyclooxygenase / colon cancer / tumon angiogenesis / chemotherapy / interferon-γ / cyclooxgenase / 5FU / celecoxib / 併用療法 / cyclooxygenase-2阻害剤 / 5-FU / VEGF |
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| 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
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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. Less
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