2007 Fiscal Year Final Research Report Summary
Cyclooxygenase-2 inhibitor is a possible new drug for treatment of gastrointestinal cancers
| Project/Area Number |
16390374
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
SUGIHARA Kenichi Tokyo Medical and Dental University, 大学院・医歯学総合研究科, Professor (10171167)
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| Co-Investigator(Kenkyū-buntansha) |
ENOMOTO Masayuki Tokyo Medical and Dental University, 大学院・医歯学総合研究科, Lecturer (60301165)
UETAKE Hiroyuki Tokyo Medical and Dental University, 大学院・医歯学総合研究科, Associate Professor (60311651)
HIGUCHI Tetsuro Tokyo Medical and Dental University, 医学部・附属病院, Assistant (90334416)
YOSHIMURA Tetsunori Tokyo Medical and Dental University, 医学部・附属病院, Assistant (00431908)
KOBAYASHI Hirotoshi Tokyo Medical and Dental University, 医学部・附属病院, Assistant (70451953)
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| Project Period (FY) |
2004 – 2007
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| Keywords | cyclooxygenase / COX-2 inhibitor / colorectal cancer / gastric cancer / lung metastasis / iver metastasis |
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| Research Abstract |
COX-2 expression of gastrointestinal cancers: <Study1> We investigate COX-2 and Loxs of colorectal cancer. Of 91 primary colorectal cancers, Loxs mRNA was found in 72.5%. High expression of Loxs and COX-2 protein were found by immunohistochemical staining in 68.7% and 79.1%, respectively. The high expression of Loxs protein was correlated with that of COX-2 protein. Arachdonic acid is metabolized either by Loxs or COX. This study showed Loxs is up-regulated in colorectal cancer, and inhibition of Loxs as well as COX-2 may prevent development of colorectal cancer. <Study2> Expression of VEGF, COX-2 and CD34 for microvessel density was investigated in 169 gastric cancers. COX-2 and VEGF were highly expressed in 36.7% and 50.3%, respectively. Positive relation was found between VEGF and COX-2 expression and between VEGF and CD34 expression. VEGF expression was correlated with depth of invasion, metastatic lymph nodes, lymphatic and venous invasion and TNM stage. Patients with positive VEG
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F staining showed lower disease free survival and overall survival than those with negative VGEF staining. In multivariate analysis, tumor location, depth of invasion and lymph node metastasis were shown to be independent prognostic factor. VEGF expression may be a valuable prognostic factor in gastric cancer.
COX-2 inhibitors and suppression of tumor growth: <Study1> We investigate the microvascular structure of small lung metastases and the effect of JTE-522, a selective COX-2 inhibitor, on the angiogenesis of pulmonary metastases from colorectal cancer in rats. The tail veins of 20 rats were injected with a tumor suspension of a rat colon cancer cell line. Three weeks later, pulmonary vascular resin corrosion casts were taken and the vascularity of metastases was studied with using stereo and scanning electron microscopes. In addition, we investigated the effect of 0, 10 and 30 mg/kg/day of JTE-522 on the angiogenesis of pulmonary metastases in 3 groups of 5 rats. The diameter of tumor vessels and the size of lung metastases significantly and positively correlated with neovascularization in 35 metastatic tumors. JTE-522 reduced the size of metastatic tumors and the diameter of tumor vessels. Selective COX-2 inhibitors may interfere the growth of hematogenous metastatic tumors by disrupting neovascularization. <Study2> We investigated the tumor vessel of metastatic liver tumors and the effect of Meloxicam, a selective COX-2 inhibitor, on growth and microvasculature of small metastatic liver tumors in rats. Metastatic liver tumors were produced by intraportal inoculation of RCN-H4 cells in 40 rats. Microvasculature of liver metastasis was studied by scanning electron microscopy and stereomicroscopy. Microvascular casts were produced by perfusion via the abdominal aorta 14 days after tumor inoculation. Meloxicam was administered in four groups with a dose of 0, 0.6, 1.0, 3.0 mg/kg/day orally 5 days per week from the day of inoculation of RCN-H4 cells for 2 weeks. The number of metastatic tumors and was less in the Meloxicam-treated groups in comparison with dose dependent fashion. From these observations, Meloxicam interfered growth of metastatic liver tumors through anti-angiogenic activity. Meloxicam may have therapeutic potential for liver tumors of colorectal carcinoma. Less
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