Antisense inhibition of urokinase reduces spread of human ovarian cancer in mice.

Urokinase-type plasminogen activator (uPA) is a protease involved in the process of tissue remodelling and cell migration in vitro. To explore whether uPA is a prerequisite for human ovarian cancer spread in vivo the expression of uPA was suppressed in human ovarian cancer cells by antisense phosphorothioate oligonucleotides (PS-ODN). The suppression of uPA expression was dependent on PS-ODN concentration and only observed 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 concert with liposomes as studied by fluorescently-labeled PS-ODNs using flow cytofluorometry and laser scanning microscopy. uPA-deprived cancer cells exhibited a significantly reduced invasive capacity in vitro compared with untreated cancer cells or cells treated with control PS-ODNs (P = 0.003). The intraperitoneal spread of the cancer cells in vivo was significantly diminished when nude mice were treated with uPA antisense PS-ODNs in comparison with control mice (P = 0.009). These results suggest that uPA expression may be required for spread of human ovarian cancer and that its inhibition could provide a therapeutic approach.