Bystander or no bystander for gene directed enzyme prodrug therapy

Abstract

Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC), and bacterial nitroreductase (NfsB) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), and their respective derivatives.

Figure 1

Gene directed enzyme prodrug therapy (GDEPT). Gene delivery to tumour or stromal cells is followed by gene expression and subsequent administration of a non-toxic prodrug. The therapeutic gene encodes an enzyme that converts the prodrug to a cytotoxin, leading to cell death. Surrounding cells may also be killed due to the local bystander effect, or, in the absence of a bystander effect, due to the collapse of the vasculature.