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Abstract
Abstract Purpose: Diffuse-type gastric carcinoma carries the highest mortality because of a frequent metastasis to lymph node. S1, a 5-fluorouracil (5-FU) analog, is clinically available for gastric cancer at advanced stage. Fibroblast growth factor receptor 2 (FGFR2) is required for the proliferation of diffuse-type gastric carcinoma. The objective of this study is to clarify the benefit of a combination of S1 and kinase inhibitors including FGFR2 inhibitor Ki23057 in gastric cancer. Experimental Design: OCUM-2MLN and KATO-III were derived from diffuse-type gastric carcinoma. MKN-7 and MKN-74 were derived from intestinal-type gastric carcinoma. MTT assay was used to examine the growth-inhibitory activity of 5 small-synthetic molecules including Ki23057, Sunitinib, Glivec, Lapatinib, or SU11274, in cells cultured with 5-FU. Combination effects of 5-FU with Ki23057 on proliferation, apoptosis, and mRNA expression were examined. S1 and/or Ki23057 were administered to murine models of diffuse-type gastric carcinoma created by the orthotopic inoculation of OCUM-2MLN cells. Results: Ki23057 at 100 nM significantly (p<0.01) inhibited the proliferation, and decreased the phosphorylation of FGFR2 in diffuse-type gastric carcinoma cells, but not in intestinal-type gastric carcinoma. Ki23057 showed synergistic anti-tumor effects for diffuse-type gastric carcinoma cells in combination with 5-FU using CalcuSyn analysis, but Sunitinib, Glivec, Lapatinib, and SU11274 did not. The combination of Ki23057 and 5-FU decreased DPD expression, and increased apoptosis rates, and p21 expression level of diffuse-type gastric carcinoma cells. The combined administration of S1 and Ki23057 significantly (p<0.05) decreased orthotopic tumors as well as lymph node metastasis more effectively than S1 alone. Conclusion: The combined treatment with 5-FU and Ki23057 produced synergistic anti-tumor effects, and is a therapeutically promising for diffuse-type gastric carcinoma treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2552. doi:10.1158/1538-7445.AM2011-2552
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