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Research Paper
Use of Methotrexate-Based Peptide Substrates to Characterize the Substrate Specificity of Prostate-Specific Membrane Antigen (PSMA)
Annastasiah Mhaka, Alyssa M. Gady, D. Marc Rosen, Kin-Ming Lo, Steven D. Gillies and Samuel R. Denmeade
volume 3 | issue 6
june 2004Pages: 551-558
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Prostate-Specific Membrane Antigen (PSMA) is a glutamate carboxypeptidase II that is highly expressed by both normal and malignant prostate epithelial cells and by the neovasculature of many tumor types but is not expressed by endothelial cells in normal tissue. PSMA possesses the hydrolytic properties of an N-acetylated ?-linked acidic dipeptidase (NAALADase) and also functions as a pteroyl poly-?-glutamyl carboxypeptidase (i.e. folate hydrolase). Therefore, PSMA can be targeted for activation of peptide-based prodrugs within the extracellular fluid of prostate cancers. In this study, methotrexate-based peptide analogs were evaluated to identify PSMA selective substrates that are also stable to non-specific hydrolysis in human and mouse plasma. These methotrexate analogs were also characterized for in vitro toxicity against PSMA and non-PSMA producing human cancer cell lines. Analogs containing ?-linked glutamate residues were most efficiently hydrolyzed by PSMA, but were unstable in plasma. Analogs containing both ?- and ?-linked acidic amino acids were less efficiently hydrolyzed by PSMA but were most stable in plasma. Analogs were 5-10 fold more selectively toxic in vitro in the presence of active PSMA. These studies have identified PSMA selective, plasma stable peptide substrates that can be incorporated into prodrugs targeted for activation by PSMA within prostate cancer sites.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.