The novel anti-tumour agent oxamflatin differentially regulates urokinase and plasminogen activator inhibitor type 2 expression and inhibits urokinase-mediated proteolytic activity

Cell surface, urokinase (u-PA)-mediated, plasminogen activation has recentl y been recognised as a process integral to extracellular matrix degradation . The primary inhibitor of u-PA activity in the extracellular matrix is pla sminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor. T he malignant metastatic phenotype is associated with excessive and uncontro lled, tumour cell-associated, u-PA-mediated, extracellular matrix degradati on. Inhibition of the malignant metastatic phenotype via induction of PAI-2 expression and/or inhibition of u-PA expression may represent a novel mean s via which the metastatic phenotype can be arrested. Agents capable of ind ucing PAI-2 and/or inhibiting u-PA activity may restrict u-Pa-mediated tumo ur cell proteolysis and facilitate in the development of therapeutic strate gies to combat malignant disease. We have identified the hydroxamic acid de rivative oxamflatin, previously noted to revert the malignant phenotype in K-ras-transformed NIH-3T3 cells, as capable of upregulating PAI-2 and simul taneously suppressing u-PA expression in two different cell systems. In add ition, zymographic analysis indicated that oxamflatin treatment results in a significant reduction in u-PA proteolytic activity in both HT-1080 fibros arcoma and U-937 histiocytic lymphoma cells. We postulate that oxamflatin r epresents a novel means by which induction of PAI-2 and concomitant inhibit ion of u-PA gene and protein expression can be achieved and may be of benef it in inhibiting the malignant metastatic phenotype. (C) 2000 Elsevier Scie nce B.V. All rights reserved.