Urokinase-type plasminogen activator (uPA) is a
serine protease associated with tissue remodeling, cellular invasiveness, matrix degradation and
tumor growth. Over-expression of uPA by the rat
prostate-cancer cell line Dunning R3227, Mat LyLu, results in increased
tumor metastasis to several non-skeletal and skeletal sites. Histological examination of these skeletal lesions has shown them to be primarily osteoblastic. In the present study we examined the capacity of a selective inhibitor of uPA enzymatic activity, 4-iodo
benzo[b]thiophene-2-carboxamidine (B-428), to prevent the development of
tumor growth and invasiveness in a syngeneic model of rat
prostate cancer using a Dunning R3227 cell line over-expressing rat uPA. Male Copenhagen rats were inoculated s.c. with experimental cells into the right flank and continuously infused i.p. with either vehicle alone or uPA inhibitor for 2 to 3 weeks. Animals were killed at timed intervals and evaluated for the development of
tumor growth and
metastasis. Serum from these animals was collected to examine any signs of nephrotoxicity. Control animals receiving vehicle alone developed large
tumors at the site of inoculation as well as macroscopic
metastases in the lungs, kidney, spleen and lymph nodes. In contrast, experimental animals receiving uPA inhibitor showed a marked decrease in primary
tumor volume and weight as well as in the development of
tumor metastases. The occasional
tumor metastases observed after infusion of
B-428 were significantly smaller than those observed in vehicle controls. These effects of
B-428 were found to be dose-dependent without any adverse effects on the renal function of experimental animals. These studies demonstrate that uPA-specific inhibitors can decrease primary
tumor volume and invasiveness as well as
metastasis in a model of
prostate cancer where uPA has been implicated as a major pathogenetic factor.