[The inhibitory effect of nafamostat mesilate (FUT-175) on liver metastasis].
Basic investigation of inhibitory effect on metastasis of nafamostat mesilate (FUT-175) which is a kind of serine protease inhibitors, was performed. Colon 26 cells were injected to the portal vein of CDF1 mice. FUT-175 at doses of 0.3, 1.0, 3.0, 10.0 mg/kg was injected intravenously every 7 day. Mice were sacrificed on day 21, and metastasis of liver surface were measured. The dose dependent reduction of metastasis was observed and reduction of metastasis of mice treated at a dose of 10.0 mg/kg was significant. FUT-175 showed no cytotoxicity at doses of 10(-5) M or less in vitro, and blood concentration of mice, treated at a dose of 10.0 mg/kg, was 2.67 x 10(-7) M. The results showed that inhibitory effect of FUT-175 on metastasis was not caused by direct cytotoxicity. FUT-175 at 2.67 x 10(-7) M in vitro can inhibit only thrombin and plasmin at nearly 50%, and can not inhibit platelet aggregation and collagenase directly. Possible mechanism of inhibition of metastasis is that FUT-175 inhibited both thrombin-mediated platelet aggregation and plasmin-mediated collagenase activation, that arrest and extravasation in cancer cells were inhibited. If protease inhibitor is administered continuously and immediately after surgery, liver metastasis may be prevented.
Kimura
T
T
First Department of Surgery, Okayama University Medical School, Japan.
Fuchimoto
S
S
Iwagaki
H
H
Orita
K
K
D000818:Animals; D001550:Benzamidines; D017364:Collagenases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology; D005341:Fibrinolysin / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D009360:Neoplastic Cells, Circulating; D010974:Platelet Aggregation; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013917:Thrombin / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001550:Benzamidines; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D013917:Thrombin; D005341:Fibrinolysin; D017364:Collagenases; C032855:nafamostat