ENZYMES AND TARGETED ACTIVATION OF PRODRUGS

Currently, 5-7% of the drugs approved worldwide can be classified as prodrugs, and approximately 15% of all new drugs approved each year were prodrugs. Activation of prodrugs can involve many endogenous enzymes including CYP450, DT-diaphorase, tyrosinase, CE, and P-glucuronidase. Exogenous enzymes can also be used to activate prodrugs as in antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), virus-directed enzyme prodrug therapy (VDEPT), and polymer-directed enzyme prodrug therapy (PDEPT). This chapter provides an overview of the enzymes used in prodrug activation with emphasis to their structure, distribution, and mechanism of activation for typical prodrugs. There are a wide variety of enzymes (primarily from bacterial sources), such as carboxypeptidase G2 (CPG2), ß-glucuronidase, and nitroreductase (NTR), that have been used in ADEPT, GDEPT, and VDEPT approaches.