Although many agents that interfere with clotting mechanisms have been investigated for their potential to inhibit metastasis, their toxicity has prevented administration of sufficiently high doses to achieve inhibition of metastasis in clinical trials. Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, inhibited liver metastasis in a CDF1 mice model with colon 26 adenocarcinoma cells. The apparently dose-dependent inhibitory effect was seen 21 days after all of the doses tested (0.3, 1.0, 3.0 and 10.0 mg/kg for 7 days) but the effect was only statistically significant (P less than 0.01) at the highest dose. The blood concentrations 3 min after dosing were less than 10(-6) M for all of the doses tested. At a concentration of 10(-5) M or less nafamostat mesilate was not cytotoxic towards colon 26 cells in vitro. The results indicate that it may not be difficult to achieve blood nafamostat mesilate concentrations that inhibit metastasis in mouse liver. Possible mechanisms of nafamostat mesilate are inhibition of extravasation and invasion of cancer cells, inactivation of collagenase due to inhibition of plasmin activity and inhibition of the formation of the cancer cell thrombus, and arrest in the capillaries through inhibition of thrombin activity. These preliminary results suggest that peri-operative administration of nafamostat mesilate may prevent metastasis into the liver after surgery for gastrointestinal malignancies.
As it was impossible to increase the dose of suramin intravenously because of side effects, administration of suramin by another method, such as subcutaneous injection around the tumor, may increase the concentration of suramin in the tumor tissue and promote the anti-tumor effect of suramin.
In the following study, we investigated whether ex vivo perfusion of canine pancreaticoduodenal allografts prior to transplantation using a class‐II‐specific monoclonal antibody (MoAb) OKIa1) could prevent acute rejection. Untreated grafts were rejected within 6 days after transplantation, and all of these recipients suffered severe hyperglycemia. In contrast, in recipients who received grafts which underwent ex vivo class‐II‐specific MoAb perfusion treatment, the mean urinary amylase levels were sustained significantly higher (11733 ± 4493 vs. 3274 ± 2108 U/L on day 7, P < 0.005), and mean fasting blood glucose (FBG) levels remained within the normal range (13.4 ± 5.8 vs. 23.4 ± 3.9 mM on day 7, P < 0.0005). Low doses of cyclosporin A (CsA) were necessary in order to maintain lower FBG levels. Histopathology analysis on day 7 after transplantation showed that endotheliitis and necrosis were much less prominent in the MoAb‐treated grafts. In the light of our results, we conclude that ex vivo perfusion of canine pancreaticoduodenal allografts using a class‐II‐specific MoAb is effective in delaying the onset of acute rejection, and low doses of CsA could extend this effect.
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