We developed and tested a novel enzyme/prodrug strategy for cancer gene therapy using Carboxypeptidase A (CPA) to enzymatically convert the prodrug methotrexate-Alpha-phenylalanine (MTX-Phe) to methotrexate (MTX). CPA is normally synthesized as a zymogen that requires proteolytic removal of its pro- peptide by trypsin in order to gain catalytic activity. In Specific Aim I in order to use CPA as a therapeutic gene we engineered a battery of mutant forms of ...
Treatment of advanced breast cancer with standard chemotherapy is often hampered by both local an systemic toxicities. We, therefore, propose to develop an enzyme / prodrug strategy for cancer gene therapy based upon methotrexate prodrugs and the enzyme carboxypeptidase A. To that end we have developed and characterized in vitro mutant forms of carboxypeptidase A which are activated in a trypsin independent manner. Enzymatic analysis ...
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