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

硬癌是所有胃癌中死亡率最高的。据报道，不良预后与编码成纤维细胞生长因子受体2型（FGF-R2）的K-samll扩增有关。转化生长因子β受体（transforminggrowthfactor β receptor，TGF 3-R）也被报道与胃硬癌的恶性潜能有关。OCUM-2 MD 3和OCUM-8来源于硬癌。MKN-7、MKN-45和MKN-74细胞来源于非硬癌。通过计算癌细胞的数量来确定FGF-R2自磷酸化抑制剂Ki 23057对细胞生长的体外作用。检测Ki 23057对胃癌细胞MAP激酶和PI 3激酶信号通路及凋亡通路的影响。体外实验观察TGFβ-R抑制剂A-77对细胞粘附能力、侵袭能力及粘附分子表达的影响。在体内实验中，将Ki 23057或A-77口服给药至腹膜播散的小鼠模型，在OCUM-2 MD 3和OCUM-8细胞中发现K-samII扩增，但在MKN-7、MKN-45或MKN-74细胞中未发现K-samII扩增。Ki 23057对硬癌细胞的增殖有明显的抑制作用，而对非硬癌细胞的增殖无明显影响。Ki 23057降低了K-samll/FGF-R2、ERK和Akt的磷酸化，并增加了硬癌细胞系的凋亡。口服Ki 23057给药显著（p<0.001）延长了注射OCUM-2 MD 3硬癌细胞后腹膜播散的小鼠的存活。A-77给药导致腹膜播散小鼠（中位生存时间; 51天）的预后显著（p<0.01）优于对照组（中位生存时间; 25天）。因此，A-77显著（p<0.01）降低了转移性淋巴结的重量和数量。

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.