Novel bi- and trifunctional inhibitors of tumor-associated proteolytic systems.

Several proteases including matrix metalloproteinases (MMPs), cysteine proteases (CPs), and serine proteases (e.g. the uPA/plasmin system) are involved in cancer cell invasion and metastasis. In the present study we designed multifunctional inhibitors that efficiently inhibit the enzymatic activity of MMPs, CPs and uPA/uPA-receptor interaction. Recombinant inhibitors were at first produced in E. coli expression system and characterized in vitro. Inoculation of the ovarian cancer cells expressing these multifunctional inhibitors into the peritoneum cavity of nude mice resulted in a significant reduction of tumor burden and spread compared to a vector-transfected control cell line.