ANTISENSE INHIBITION OF UROKINASE REDUCES SPREAD OF HUMAN OVARIAN-CANCER IN MICE

Urokinase-type plasminogen activator (uPA) is a protease involved in t he process of tissue remodelling and cell migration in vitro. To explo re whether uPA is a prerequisite for human ovarian cancer spread in vi vo the expression of uPA was suppressed in human ovarian cancer cells by antisense phosphorothioate oligonucleotides (PS-ODN). The suppressi on of uPA expression was dependent on PS-ODN concentration and only ob served in the presence of liposomes. This phenomenon seemed to be due to the fact that PS-ODNs were taken up by the cancer cells only in con cert with liposomes as studied by fluorescently-labeled PS-ODNs using flow cytofluorometry and laser scanning microscopy. uPA-deprived cance r cells exhibited a significantly reduced invasive capacity in vitro c ompared with untreated cancer cells or cells treated with control PS-O DNs (P=0.003). The intraperitoneal spread of the cancer cells in vivo was significantly diminished when nude mice were treated with uPA anti sense PS-ODNs in comparison with control mice (P=0.009). These results suggest that uPA expression may be required for spread of human ovari an cancer and that its inhibition could provide a therapeutic approach .