Methods to improve efficacy in suicide gene therapy approaches: targeting prodrug-activating enzymes carboxypeptidase G2 and nitroreductase to different subcellular compartments.

Abstract

AbstractCurrent cancer chemotherapy strategies are often hampered by the lack of tumor selectivity, resulting in unwanted damage to healthy tissue. Gene-directed enzyme-prodrug therapy (GDEPT) (1) and virus-directed enzyme-prodrug therapy (VDEPT) (2) are suicide gene therapy approaches that aim to deliver cytotoxic agents to tumor cells in a specific manner, thus improving the selectivity of chemotherapy and protecting normal cells from adverse side effects. In the first step, a gene encoding a foreign enzyme is delivered to tumor cells (see Fig. 1). The aim is to express the enzyme only in the tumor cells and then administer a prodrug. Prodrugs are small molecules that are nontoxic to normal cells, but are converted to potent cytotoxic agents in tumors. In GDEPT, the foreign enzyme performs this conversion, so if the enzyme is successfully targeted, the toxin will only be produced in the tumor, sparing normal tissues from excessive damage. Schematic diagram of GDEPT. (A) Delivery of the gene encoding the prodrug-activating enzyme by recombinant viruses. (B) expression of the enzyme by cells that have been transduced. Upon prodrug administration, the enzyme converts the prodrug into the active, cytotoxic drug (magnified square), which spreads to adjacent cells that do not express the enzyme (bystander effect). (C) The cytotoxic drug induces cell death in expressing and nonexpressing cells. KeywordsThymidine KinaseBystander EffectHerpes Simplex VirusCPG2 ActivityDirect Cell KillingThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.