Prodrug-activating systems in suicide gene therapy.

Abstract

Cancer chemotherapy encompasses a large number of well-documented and clinically established methods for the treatment of malignant diseases. However, the efficacy of these approaches is often hampered by an insufficient therapeutic index, lack of specificity, and the emergence of drug-resistant cell subpopulations. One approach aimed at enhancing the selectivity of cancer chemotherapy for solid tumors relies on the application of gene therapy technologies. Gene therapies are techniques for modifying the cellular genome for therapeutic benefit. In cancer gene therapy, both malignant and nonmalignant cells may be suitable targets. The possibility of rendering cancer cells more sensitive to chemotherapeutics or toxins by introducing “suicide genes” was suggested in the late 1980s. This approach has two alternatives: toxin gene therapy, in which the genes for toxic products are transfected directly into tumor cells; and enzyme-activating prodrug therapy, in which the transgenes encode enzymes that activate specific prodrugs to create toxic products. The latter approach, known as gene-directed enzyme prodrug therapy (GDEPT) (1, 2) or virus-directed enzyme prodrug therapy (VDEPT) (3), may be used in isolation or combined with other strategies, such as the biotherapies described elsewhere in this Perspective series. VDEPT using selectively replicating viruses as vectors represents a promising means to target suicide genes specifically to tumor cells, an approach that is only beginning to be explored (for examples, see Hermiston, this Perspective series, ref. 4). GDEPT and VDEPT are two-step treatments for solid tumors (Figure ​(Figure1).1). In the first step, the gene for a foreign enzyme is delivered and targeted in a variety of ways to the tumor where it is to be expressed. In the second step, a prodrug is administered that is selectively activated to the drug by the foreign enzyme expressed in the tumor. Ideally, the gene for the enzyme should be expressed exclusively in the tumor cells and should reach a concentration sufficient to activate the prodrug for clinical benefit. The catalytic activity of the expressed protein must be adequate to activate the prodrug under physiological conditions. Because expression of the foreign enzymes will not occur in all cells of a targeted tumor in vivo, a bystander effect (BE) is required, whereby the prodrug is cleaved to an active drug that kills not only the tumor cells in which it is formed, but also neighboring tumor cells that do not express the foreign enzyme (5). Figure 1 GDEPT, a form of suicide gene therapy, aims to maximize the effect of a toxic drug and minimize its systemic effects by generating the drug in situ within the tumor. In the first step in this procedure, the gene for an exogenous enzyme is delivered and ... The genes can be engineered to express their products either intracellularly or extracellularly in the recipient cells (6). There are potential advantages to each approach. When the enzyme is intracellularly expressed, the prodrug must enter the cells for activation, and subsequently the active drug must diffuse through the interstitium across the cell membrane to elicit a BE. Cells in which the enzyme is expressed (tethered to the outer surface) are able to activate the prodrug extracellularly. A more substantial BE could therefore be generated with extracellular gene product expression, but spread of the active drug into the general circulation is a possible disadvantage (1, 6).