A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo

Urokinase plasminogen activator (uPA) plays an important role in the progre ssion of several malignancies including breast cancer. We have identified a noncompetitive antagonist of the uPA-uPAR interaction derived from a nonre ceptor binding region of uPA (amino acids 136-143). This 8-mer capped pepti de (Angstrom 6) inhibited breast cancer cell invasion and endothelial cell migration in a dose-dependent manner in vitro without altering cell doublin g time. Intraperitoneal administration of Angstrom 6 resulted in a signific ant inhibition of tumor growth and suppressed the development of lymph node metastases in several models of breast cancer cell growth and metastasis, Large areas of tumor necrosis and extensive positive staining by TUNEL were observed on histological and inmunohistochemical analysis of experimental tumor sections from Angstrom 6-treated animals.;is treatment also resulted in a decrease in factor VIII-positive tumor microvessel hot-spots. These re sults identify a new epitope in uPA that is involved in the uPA-uPAR intera ction and indicate that an antagonist based on this epitope is able to inhi bit tumor progression by modulating the tumor microenvironment in the absen ce of direct cytotoxic effects in vivo.