Chapter 8 - Gene-directed enzyme prodrug therapy

Abstract

The chapter focuses on the development of new and improved prodrugs for gene-directed enzyme prodrug therapy (GDEPT). Cancer chemotherapy encompasses a vast number of established clinical methods for the treatment of persons with malignant diseases. However, the efficacy of such methods is frequently hampered by an insufficient therapeutic index, and the emergence of drug-resistant cell subpopulations. Gene therapy is broadly defined as a technology aimed at modifying the genetic component of cells for therapeutic benefits. In cancer gene therapy, both malignant and nonmalignant cells can be targeted for therapeutic gain. In GDEPT, genes for foreign enzymes that can activate specific prodrugs are transduced into cancer cells. As current vectors for gene delivery are incapable of conferring expression of the foreign enzyme in all tumor cells, a bystander effect (BE) is required, whereby the prodrug is cleaved to an active drug that kills neighboring tumor cells that are not expressing the foreign enzyme. The design of GDEPT systems requires prodrugs tailored for the use of the foreign enzymes selected. Intracellular transport is required if the enzyme is to be intracellularly expressed. The prodrug should have very limited cytotoxicity, whereas the activated drug should be as potent as possible. There should be effective activation of the prodrug by the expressed enzyme with favorable activation kinetics, and ideally, the drugs released should kill both proliferative and quiescent cells, and should induce a BE.