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Inhibitors of Urokinase Reduce Size of Prostate Cancer Xenografts in Severe Combined Immunodeficient Mice¹

Departments of Urology [J. J., R. W. K.] and Physiology and Molecular Medicine [J. J., R. S.], Medical College of Ohio, Toledo, Ohio 43699-0008, and Department of Chemistry, The University of Toledo, Toledo, Ohio 43606-3390 [E. S-J.]

Proteolytic enzymes are required to mediate tumor cell invasion and metastasis. The urokinase plasminogen activator (uPA) is commonly overexpressed by many human cancers. Therefore, uPA is a logical target to inhibit cancer invasion and metastasis. However, uPA inhibitors also reduce tumor growth. We used a mutated form of plasminogen activator inhibitor type 1 to conform a correlation between the inactivation of uPA and tumor size; we have compared these results with the action of p-aminobenzamidine and amiloride, known inhibitors of uPA. Our results show that blocking uPA by uPA inhibitors reduces tumor size in experimental animals. Our molecular simulation of docking inhibitors to the urokinase reveals that all tested small molecule inhibitors bind in proximity of uPA's specificity pocket, a critical site for future search of novel anticancer uPA inhibitors.

¹ This work was supported by a grant from American Diagnostica, Inc., Greenwich, CT.

² To whom requests for reprints should be addressed, at Department of Urology, Medical College of Ohio, Toledo, OH 43699-0008. Phone: (419) 381-3691; Fax: (419) 381-3168; E-mail: jerzy@golemxiv.dh.mco.edu; http://golemxiv.dh.mco.edu/~jerzy/.

Received 10/22/96. Accepted 12/14/96.

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