title: A novel transforming growth factor beta receptor kinase inhibitor, A-77, prevents the peritoneal dissemination of scirrhous gastric carcinoma.
abstract: OBJECTIVE
  Transforming growth factor beta receptor (TGFbeta-R) is reported to correlate with the malignant potential of scirrhous gastric carcinoma. The aim of the current study is to clarify the possibility of molecular target therapy with a TGFbeta-R inhibitor, A-77, for the treatment of peritoneal dissemination of scirrhous gastric cancer.
  
  
  METHODS
  Three scirrhous gastric cancer cell lines and two fibroblasts were used. For in vivo experiments, the A-77 was administered i.p. to mouse models of peritoneal dissemination. The influences of A-77 on the adhesion ability, invasion ability, and the expression of adhesion molecules were examined in vitro.
  
  
  RESULTS
  The A-77 administration resulted in a significantly (P < 0.01) better prognosis for the mice with peritoneal dissemination (median survival time, 51 days), compared with the control (median survival time, 25 days). A-77 therefore significantly (P < 0.01) decreased the weight and number of metastatic nodes. The adhesive ability and invasion ability of cancer cells were significantly decreased by A-77. A-77 decreased the expression of alpha(2), alpha(3), and alpha(5) integrins in gastric cancer cells. The histologic findings showed the degree of fibrosis to be less in the tumors treated by A-77. A-77 decreased the growth of fibroblast and invasion-stimulating activity of fibroblasts on cancer cells.
  
  
  CONCLUSIONS
  The TGFbeta-R inhibitor, A-77, decreased the expression of integrins in cancer cells and the proliferation of fibroblasts, which resulted in the decreased adhesive and invasive abilities of scirrhous gastric cancer cells to peritoneum. A-77 is thus considered to be useful for the inhibition of peritoneal dissemination of scirrhous gastric carcinoma.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kawajiri
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: Satoru
authors.initials: S
authors.lastname: Takemura
authors.forename: Manabu
authors.initials: M
authors.lastname: Node
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamashima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kajimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.forename: Masaichi
authors.initials: M
authors.lastname: Ohira
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D002293:Adenocarcinoma, Scirrhous / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010534:Peritoneal Neoplasms / Q000517:prevention & control / Q000556:secondary*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary
chemical_list: C531424:A-77 compound; D000970:Antineoplastic Agents; D016023:Integrins; D011720:Pyrazoles; D011804:Quinolines; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein