Suramin potently inhibits the enzymatic activity of PSM

BACKGROUND. The polysulfonated napthlyurea suramin has shown significant an titumor activity in patients with hormone-refractory metastatic prostate ca ncer. The mechanism by which suramin exerts this effect is unknown. In 1993 , prostate-specific membrane antigen (PSM) was identified as a prostate bio marker that is elevated in hormone-refractory and metastatic prostate cance r. PSM is a glutamate exocarboxypeptidase capable of cleaving the terminal alpha-linked glutamate from the dipeptide N-acetyl-aspartyl-glutamate (NAAG ) and the gamma-linked glutamates from folate polyglutamate. METHODS. Using a NAAG hydrolytic radioenzymatic assay, we tested whether su ramin had any effect on the enzymatic activity of PSM. RESULTS. We demonstrate that suramin potently inhibits the enzymatic activi ty of PSM with a K-i = 15 nM and 68 nM for the membrane-associated and solu ble forms of PSM, respectively. In addition, we show that suramin inhibitio n of PSM enzyme activity displays the kinetics of a classic competitive inh ibitor. CONCLUSIONS. This is one of the most potent activities described for surami n to date and may represent a portion of its pharmacologic and/or toxicolog ical mechanism of action. (C) 2000 Wiley-Liss, Inc.