REDUCTION OF TUMOR-ASSOCIATED FIBRINOLYTIC-ACTIVITY BY ANTIMETASTATIC DOSAGES OF 2 RU(II)-DMSO COMPLEXES IN MICE BEARING LEWIS LUNG-CARCINOMA

Abstract

Some Ru(II)-DMSO complexes have antimetastatic properties in experimental tumors. Since plasminogen activators are thought to play an important role in the expression of cancer cell metastatic capacity, we evaluated the effect of two Ru(II)-DMSO complexes on the fibrinolytic activity of Lewis lung carcinoma. Tumor-bearing mice were given daily, for 14 days, an i.p. injection of antimetastatic dosages of cis-RuCl2(DMSO)4 (700 mg/kg/die) or trans-RUCl2(DMSO)4 (37 mg/kg/die), or vehicle. Tumor extracts obtained on day 15 from treatment groups had significantly lower (plasminogen-dependent) fibrinolytic activity than extracts from control animals (p<0.001). Urokinase inhibitor activity in tumor extracts did not differ among groups and did not correlate with plasminogen activator activity, Fibrin autography of control tumor extracts revealed the presence of a main fibrinolytic band co-migrating with urinary plasminogen activator (urokinase-type) and of minor bands with a higher molecular weight. In samples from animals treated with either Ru(II)-DMSO complex the most striking finding was a reduction of the band corresponding to free urokinase. These findings suggest that ruthenium complexes decrease the fibrinolytic activity of tumor cells by reducing urokinase production rather than by enhancing inhibitor production. Treatment of tumor-bearing mice with cis-RuCl2(DMSO)4 at a dosage equimolar to the trans isomer, neither reduced metastasis formation nor decreased plasminogen activator activity of tumor extracts. The depression of tumor-associated proteolytic activity could contribute to the antimetastatic properties of ruthenium complexes.