Combination effect of a TGF-beta receptor kinase inhibitor with 5-FU analog S1 on lymph node metastasis of scirrhous gastric cancer in mice.
Transforming growth factor-beta (TGF-beta) signals are closely associated with the distant metastases of gastric cancer. The aim of this study was to clarify the effect of a TGF-beta receptor I (TbetaR-I) phosphorylation inhibitor, Ki26894, in combination with anticancer drugs, on the lymph node (LN) metastasis of scirrhous gastric cancer. A novel TbetaR-I kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at the ATP binding site of TbetaR-I. S1 is a 5-fluorouracil analog. The human scirrhous gastric cancer cell line OCUM-2MLN and the human gastric fibroblasts NF-33 were used. OCUM-2MLM cells in the upper well and NF-33 cells in the lower well were co-incubated with or without Ki26894. The proliferation of OCUM-2MLN cells was significantly stimulated by co-culture with NF-33 cells. Ki26894 significantly suppressed the growth interactions between OCUM-2MLN cells and NF-33 cells. Gastric cancer models established by orthotopic inoculation of OCUM-2MLN cells showed diffusely infiltrating gastric adenocarcinoma accompanied by LN metastases. We divided these mice into four groups, (control vehicle, Ki26894, S1, Ki26894 plus S1), and examined the effect of Ki26894 and/or S1 on phosphorylation of Smad2, tumor size, LN metastases, and lymphatic involvements. Ki26894 inhibited the Smad2 phosphorylation of cancer cells and decreased the extent of lymphatic involvement, compared with the control or S1 only group. The Ki26894 plus S1 administration group significantly suppressed tumor growth and decreased LN metastasis more effectively than either alone. These findings suggested that the TbetaR-I kinase inhibitor with S1 is useful for the treatment of scirrhous gastric carcinoma with LN metastasis. (Cancer Sci 2010).
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Osamu
O
Shinto
Masakazu
M
Yashiro
Hidemi
H
Kawajiri
Kiyoshi
K
Shimizu
Toshiyuki
T
Shimizu
Atsushi
A
Miwa
Kosei
K
Hirakawa
D030201:Activin Receptors, Type I / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004338:Drug Combinations; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D010094:Oxonic Acid / Q000008:administration & dosage*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D051899:Smad2 Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005641:Tegafur / Q000008:administration & dosage*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D004338:Drug Combinations; C519257:Ki26894; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I