INHIBITION OF ESTABLISHMENT OF PRIMARY AND MICROMETASTATIC TUMORS BY A UROKINASE PLASMINOGEN-ACTIVATOR RECEPTOR ANTAGONIST

Tumor establishment and metastasis are dependent on extracellular matr ix proteolysis, tumor cell migration, and angiogenesis. Urokinase plas minogen activator (uPA) and its receptor are essential mediators of th ese processes. The purpose of this study was to investigate the effect of a recombinant human uPAR antagonist on growth, establishment, and metastasis of tumors derived from human cancer cell lines. A noncataly tic recombinant protein, consisting of amino acids 1-137 of human uPA and the CH2 and CH3 regions of mouse IgG(1) (uPA-IgG), was expressed, purified, and shown to bind specifically to human uPAR and to saturate the surface of human tumor cells which express uPAR. Daily i.p. admin istration of uPA-IgG to nude mice extended latencies of unstaged tumor s derived from Lox melanoma and SW48 colon carcinoma cells by 7.7 and 5.5 days, respectively. uPA-IgG treatment did not affect the growth of Lox or KB tumors staged to 200 mg before antagonist treatment commenc ed. The effect of uPA-IgG on the establishment of micrometastases was assessed in SCID mice. KB head/neck tumor cells were injected in the t ail vein and allowed to seed for 48 h before initiation of daily i.p. injections of uPA-IgG for 24 days. The number of lung colonies ranged between 5 and 30% of vehicle-treated mice in two separate experiments. Furthermore, a single 800 mu g dose of uPA-IgG administered 1 h prior to tail vein injection of KB cells reduced lung colony formation to j ust 3.5% of vehicle-treated SCID mice. These data demonstrate that ant agonism of uPAR arrested metastasis and inhibited the establishment of primary tumors and micrometastases, Thus, small molecule uPAR antagon ists may serve as useful adjuvant agents in combination with existing cancer chemotherapy.