A novel transforming growth factor beta receptor kinase inhibitor, A-77, prevents the peritoneal dissemination of scirrhous gastric carcinoma.
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.
Kawajiri
Hidemi
H
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Yashiro
Masakazu
M
Shinto
Osamu
O
Nakamura
Kazunori
K
Tendo
Masashige
M
Takemura
Satoru
S
Node
Manabu
M
Hamashima
Yoshio
Y
Kajimoto
Tetsuya
T
Sawada
Tetsuji
T
Ohira
Masaichi
M
Hirakawa
Kosei
K
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
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