Development of a Biological Basis for PSMA Targeting in Prostate Cancer
Annual rept. 1 Feb 2001-31 Jan 2002
CLEVELAND CLINIC FOUNDATION OH
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PSMA is a strongly expressed protein in prostate cancer, and it is a type-two membrane protein with the bulk of the molecule and enzymatic activity outside of the cell and thus is accessible to therapeutic attack. We discovered that PSMA has activity as a unique folate hydrolase, being a glutamate carboxypeptidase. We also observed that cells expressing PSMA were sensitive to killing by polygammaglutamated methotrexate while non-PSMA expressing cells were resistant. We therefore proposed to explore the biologic potential of PSMA as a therapeutic target in terms of transport and prodrug activation. Because PSMA appeared to be a broadly active carboxypeptidase we proposed to examine polygammaglutamated derivatives of cytotoxics as potential agents that then might be transported into the cell or as prodrugs that would be activated by the enzymatic activity of PSMA releasing the drug from the polygammaglutamated- linked cytotoxic at the site of the tumor.
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