INHIBITION OF THE METASTASIS OF LEWIS LUNG-CARCINOMA BY ANTIBODY AGAINST UROKINASE-TYPE PLASMINOGEN-ACTIVATOR IN THE EXPERIMENTAL AND SPONTANEOUS METASTASIS MODEL

A selective inhibitory antibody, raised against human high molecular w eight urokinase-type plasminogen activator (HMW-uPA), was examined to determine whether it would inhibit production of experimental and spon taneous lung metastasis by murine Lewis lung carcinoma (3LL) cells. Po lyclonal antibody to human uPA cross-reacts with the murine uPA and in hibits murine uPA activity. When examined with an in vitro assay syste m using a modified Boyden chamber, the anti-catalytic IgG to uPA suppr essed the invasion of tumor cells through Matrigel. Anti-uPA IgG inhib ited neither the cell proliferation nor the binding of tumor cells to Matrigel, and showed no significant suppression of chemotactic migrati on of tumor cells to fibronectin. In an in vivo spontaneous metastasis assay, multiple subcutaneous (s. c.) injections of anti-uPA IgG (up t o a concentration of 200 mu g [= 500 inhibitory unit/mouse/day]) for 7 days immediately after s. c. tumor cell inoculation significantly inh ibited the formation of lung metastasis in C57BL/6 mice in a dose-depe ndent manner. The inhibition of lung metastasis was not due to direct antitumor effects of anti-uPA IgG. In an in vivo experimental metastas is assay, multiple s. c. injections of anti-uPA IgG for 7 days after i ntravenous (i. v.) tumor cell inoculation did not reduce the number of lung tumor colonies. These results suggest that uPA more efficiently regulates the mechanism involved in the entry into vascular circulatio n of tumor cells (intravasation) than in extravasation, during the met astatic process.