Inhibition of invasion and lymph node metastasis of gastrointestinal cancer cells by R-94138, a matrix metalloproteinase inhibitor.
BACKGROUND
MMPs have been implicated in the process of metastasis. Matlystatin analogue, called R-94138, isolated from Actinomadura atramentaria, has been reported to inhibit the activity of MMP-2 and -9 specifically. In this study, we investigated the effect of R-94138 on the invasive and lymphnodal metastatic ability of gastric cancer cells.


METHODS
Three gastric cancer cell lines, MKN-28, MKN-45, MKN-74, and two colorectal cancer cell lines, HT-29, and LS174T were used. The invasion ability of these cell lines were assayed with R-94138 at the required concentration in vitro. The In vivo effect of R-94138 on lymphnode metastasis was examined passaged by orthotopic implantation.


RESULTS
All cell lines revealed activity of both 72 and 92 kDa forms of MMPs by gelatin zymography. R-94138 significantly inhibited the invasiveness of all of these cells to the extracellular matrix. The number of lymph node metastases and the amount of body weight loss were significantly decreased by intraperitoneal administration of R-94138.


CONCLUSIONS
MMP inhibitor, R-94138, has a possible application in adjunctive therapy for lymph node metastasis in gastric carcinoma.
Matsuoka
T
T
First Department of Surgery, Osaka City University Medical School, 1-4-3 Asahimachi Abeno-ku, Osaka, 545-8585, Japan.
Yashiro
M
M
Sawada
T
T
Ishikawa
T
T
Ohira
M
M
Chung
K H
KH
D000081:Acetamides / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D008207:Lymphatic Metastasis; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011480:Protease Inhibitors / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000081:Acetamides; D000970:Antineoplastic Agents; D011480:Protease Inhibitors; C117981:R 94138; D008666:Metalloendopeptidases