title: Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma.
abstract: Scirrhous gastric carcinoma (SGC) carries the highest mortality because of a frequent metastasis to lymph node (LN). S1, a 5-fluorouracil (5-FU) analog, is clinically available for gastric cancer at an advanced stage. Fibroblast growth factor receptor 2 (FGFR2) is required for the proliferation of SGC. 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. OCUM-2MLN and KATO-III were derived from SGC. MKN-7 and MKN-74 were derived from non-SGC. 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 SGC created by the orthotopic inoculation of OCUM-2MLN cells. Ki23057 at 100 nM significantly (p < 0.01) inhibited the proliferation and decreased the phosphorylation of FGFR2 in SGC cells, but not in non-SGC. Ki23057 showed synergistic antitumor effects for SGC 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 SGC cells. The combined administration of S1 and Ki23057 significantly (p < 0.05) decreased orthotopic tumors as well as LN metastasis more effectively than S1 alone. These findings suggested that the combined treatment with 5-FU and Ki23057 produced synergistic antitumor effects and is therapeutically promising for SGC treatment.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, Japan. m9312510@med.osaka-cu.ac.jp
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.forename: Osamu
authors.initials: O
authors.lastname: Shinto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masashige
authors.initials: M
authors.lastname: Tendo
authors.forename: Tasuku
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Taro
authors.initials: T
authors.lastname: Matsuzaki
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kaizaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miwa
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D002293:Adenocarcinoma, Scirrhous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D011725:Pyridines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077210:Sunitinib
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D005472:Fluorouracil; C104201:gimeracil; D000077210:Sunitinib