[The inhibitory effect of nafamostat mesilate (FUT-175) on liver metastasis]
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T Kimura1, S Fuchimoto, H Iwagaki
1First Department of Surgery, Okayama University Medical School, Japan.
Abstract:
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.
Insights
Nafamostat mesilate (FUT-175), a serine protease inhibitor, significantly reduced liver metastasis in mice. This effect was not due to direct cytotoxicity but likely involved inhibiting thrombin and plasmin activity, crucial for cancer cell extravasation.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Metastasis remains a significant challenge in cancer treatment.
- Serine protease inhibitors are being investigated for their potential anti-metastatic properties.
Purpose of the Study:
- To investigate the inhibitory effect of nafamostat mesilate (FUT-175) on liver metastasis.
- To determine the mechanism of action of FUT-175 in preventing cancer spread.
Main Methods:
- Colon 26 cells were injected into the portal vein of CDF1 mice.
- FUT-175 was administered intravenously at various doses (0.3-10.0 mg/kg).
- Liver metastasis was assessed 21 days post-injection; in vitro cytotoxicity and protease inhibition assays were performed.
Main Results:
- A dose-dependent reduction in liver metastasis was observed with FUT-175 treatment.
- Significant reduction in metastasis occurred at a dose of 10.0 mg/kg.
- FUT-175 demonstrated no direct cytotoxicity at relevant concentrations and primarily inhibited thrombin and plasmin.
Conclusions:
- Nafamostat mesilate (FUT-175) effectively inhibits liver metastasis in a preclinical model.
- The anti-metastatic effect is likely mediated by the inhibition of thrombin-mediated platelet aggregation and plasmin-mediated collagenase activation.
- Continuous administration of FUT-175 post-surgery may offer a strategy to prevent liver metastasis.
