A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for Scirrhous gastric cancer.
OBJECTIVE
Scirrhous gastric carcinoma carries the highest mortality of all gastric cancers. The poor prognosis is reported to be associated with K-samII amplification, which encodes fibroblast growth factor receptor type 2 (FGF-R2). Ki23057, a newly developed small molecule-acting K-samII/FGF-R2 autophosphorylation inhibitor, is a tyrosine kinase inhibitor that competes with adenosine triphosphate for the binding site. The aim of the current study is to clarify the possibility of molecular target therapy with Ki23057 for treating scirrhous gastric cancer.


METHODS
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 nonscirrhous carcinomas. In vitro effects of Ki23057 on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the mitogen-activated protein kinase and phosphatidylinositol 3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. For in vivo experiments, the Ki23057 was administered orally to mouse models of peritoneal dissemination.


RESULTS
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 nonscirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samII/FGF-R2, extracellular signal-regulated kinase, and Akt and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (P < .001) prolonged survival of mice with peritoneal dissemination following injection of OCUM-2MD3 scirrhous cancer cells.


CONCLUSIONS
A novel K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification.
Nakamura
Kazunori
K
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Yashiro
Masakazu
M
Matsuoka
Tasuku
T
Tendo
Masashige
M
Shimizu
Toshiyuki
T
Miwa
Atsushi
A
Hirakawa
Kosei
K
D002293:Adenocarcinoma, Scirrhous / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014183:Transplantation, Heterologous
D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C515425:Ki23057; C508053:ERBB2 protein, human