THE UROKINASE INHIBITOR P-AMINOBENZAMIDINE INHIBITS GROWTH OF A HUMANPROSTATE TUMOR IN SCID MICE

Malignant cells possess a high degree of proteolytic activity in which the plasminogen activator system plays an important role, An increase d expression of urokinase type plasminogen activator (uPA) is of signi ficance for degradation of the extracellular tumor matrix, facilitatin g invasiveness and growth. Inhibition of the active site of uPA makes it possible to evaluate the significance of uPA in tumor growth. We re port here experiments on a uPA-producing human prostate xenograft(DU 1 45) using a competitive inhibitor of uPA, p-aminobenzamidine. In vitro experiments with DU 145 cells showed that p-aminobenzamidine caused a dose-dependent inhibition of uPA activity, DU 145 cells were inoculat ed s.c. in SCID mice and, once tumors were established, treatment with p-aminobenzamidine added to drinking water was started and lasted for 23 days. Mice receiving 250 mg/kg/day of p-aminobenzamidine showed a clear decrease in tumor-growth rate compared to the nontreated mice, r esulting in 64% lower final tumor weight. In addition, uPA-antigen lev els in the membrane fractions of DU 145 tumors from p-aminobenzamidine -treated mice were found to be decreased by 59%. We also show that p-a minobenzamidine has an anti-proliferative effect in cell culture at lo w cell number, correlating with a dose-dependent decrease in uPA produ ction, In conclusion, we show that a low-molecular-weight uPA-inhibito r, p-aminobenzamidine, has a growth-inhibitory effect on a solid uPA-p roducing tumor. (C) 1995 Wiley-Liss, Inc.