| Budget Amount *help |
¥3,950,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Scirrhous gastric carcinoma carries the highest mortality of all gastric cancers. The poor prognosis reported to be associated with K-samll amplification, which encodes fibroblast growth factor receptor type 2 (FGF-R2) . Transforming growth factor β receptor (TGF3-R) is also reported to correlate with the malignant potential of scirrhous gastric carcinoma.
Five human gastric cancer cell lines were used. OCUM-2MD3 and OCUM-8 were derived from scirrhous carcinomas. MKN-7, MKN-45 and MKN-74 cells were derived from non-scirrhous carcinomas. In vitro effects of FGF-R2 autophosphorylation inhibitor, Ki23057, on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the MAP kinase and PI3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. The influences of a TGFβ-R inhibitor, A-77, on the adhesion ability, invasion ability, and the expression of adhesion molecules were examined in vitro. For in vivo experiments, the Ki23057 or A-77 was administered orally to mouse models of peritoneal dissemination.
K-samII amplification was found in OCUM-2MD3 and OCUM-8 cells, but not in MKN-7, MKN-45, or MKN-74 cells. Ki23057 significantly inhibited the proliferation of scirrhous cancer cells, but not non-scirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samll/FGF-R2, ERK and Akt, and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (p<0.001) prolonged survival of mice with peritoneal dissemination following injection of OCUM-2MD3 scirrhous cancer cells. The A-77 administration resulted in a significantly (p<0.01) better prognosis for the mice with peritoneal dissemination (median survival time; 51 days) , in comparison to the control (median survival time; 25 days) . A-77 therefore significantly (p<0.01) decreased the weight and number of metastatic nodes.
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