Effect of molecular targeting Compounds as KGFR or TGFβR Phosphorylation Inhibitors on the development of Gastric Cancer

硬化性胃癌是所有胃癌中死亡率最高的。据报道，预后不良与编码成纤维细胞生长因子受体2型(FGFR2)的K-Samll扩增有关。转化生长因子β受体(TGF3-R)也被报道与硬化性胃癌的恶性潜能有关。OCUM-2MD3和OCUM-8来源于硬癌。MKN-7、MKN-45和MKN-74细胞来源于非硬化性癌。通过计算癌细胞的数量，确定成纤维细胞生长因子-R2自磷酸化抑制剂Ki23057对细胞生长的影响。同时检测Ki23057对胃癌细胞MAP和PI3信号转导通路及细胞凋亡途径的影响。体外观察转化生长因子β-R抑制剂A-77对细胞黏附能力、侵袭能力和黏附分子表达的影响。在体内实验中，将Ki23057或A-77口服给小鼠腹膜转移模型，发现K-Samii在OCUM-2MD3和OCUM-8细胞中扩增，而在MKN-7、MKN-45和MKN-74细胞中未见扩增。Ki23057对硬化性胃癌细胞有明显的抑制作用，但对非硬化性胃癌细胞的增殖无明显影响。Ki23057使K-Samll/FGF-R2、ERK和Akt的磷酸化水平降低，细胞凋亡率增加。口服Ki23057显著延长了注射OCUM-2MD3硬性癌细胞后腹膜播散小鼠的存活时间(p&lt；0.001)。与对照组(中位生存期25天)相比，使用A-77的腹膜播散组小鼠的预后(中位存活时间：51天)显著改善(p&lt；0.01)。因此，A-77显著降低了转移结节的重量和数量(p&lt；0.01)。

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.