Suramin potently inhibits the enzymatic activity of PSM.
BACKGROUND
The polysulfonated napthlyurea suramin has shown significant antitumor activity in patients with hormone-refractory metastatic prostate cancer. The mechanism by which suramin exerts this effect is unknown. In 1993, prostate-specific membrane antigen (PSM) was identified as a prostate biomarker that is elevated in hormone-refractory and metastatic prostate cancer. 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 suramin had any effect on the enzymatic activity of PSM.


RESULTS
We demonstrate that suramin potently inhibits the enzymatic activity of PSM with a K(i) = 15 nM and 68 nM for the membrane-associated and soluble forms of PSM, respectively. In addition, we show that suramin inhibition of PSM enzyme activity displays the kinetics of a classic competitive inhibitor.


CONCLUSIONS
This is one of the most potent activities described for suramin to date and may represent a portion of its pharmacologic and/or toxicological mechanism of action.
Slusher
B S
BS
Guilford Pharmaceuticals, Inc., Baltimore, Maryland 21224, USA. slusher_b@guilfordpharm.com
Tiffany
C W
CW
Merion
A
A
Lapidus
R G
RG
Jackson
P F
PF
D000954:Antigens, Surface; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002852:Chromatography, Ion Exchange; D004151:Dipeptides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D008297:Male; D010710:Phosphates / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D016318:Quisqualic Acid / Q000737:chemistry; D012588:Scintillation Counting; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D000970:Antineoplastic Agents; D004151:Dipeptides; D010710:Phosphates; C027172:isospaglumic acid; D013498:Suramin; D016318:Quisqualic Acid; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II