Approaches to Gene-Directed Enzyme Prodrug Therapy (GDEPT)
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APPROACHES TO GENE-DIRECTED ENZYME PRODRUG THERAPY (GDEPT) Caroline J. Springer* and Ion Niculescu-Duvaz CRC Centre for Cancer Therapeutics at the Institute of Cancer Research 15 Cotswold Road Sutton, Surrey, SM2 5NG
1. INTRODUCTION Gene therapy for cancer may be broadly defined as a genetic technology aimed at modifying either malignant or non malignant cells for therapeutic gain. There are two “suicide” gene therapy approaches. In toxin gene therapy, genes are introduced into malignant cells and the translated protein directs killing of the tumour cells. The second is termed GDEPT (gene-directed enzyme prodrug therapy) (Niculescu-Duvaz et al., 1998) or VDEPT (virally-directed enzyme prodrug therapy) (Huber et al., 1995). The only difference between these acronyms is that the former involves both viral and nonviral vectors. This review covers the GDEPT approach to make tumour cells more sensitive to chemotherapeutic agents. 2. PRINCIPLES OF GDEPT GDEPT is a two-step treatment for solid tumours. Foreign enzymes are delivered to, and expressed in target cells where they can activate subsequently administered nontoxic prodrugs to active drugs. In the first step, a gene expressing the foreign enzyme is delivered. In the second step, a prodrug is administered that can be activated to a toxic drug by the enzyme that has been expressed in the tumour. There are a wide range of enzyme/prodrug systems which have been investigated (see Table 1). The foreign enzyme gene should be expressed exclusively, or with a relatively high ratio in tumour cells compared to normal tissues and blood, and should achieve a sufficient concentration for a clinical benefit. After gene delivery, prodrug administration must be delayed to permit protein expression in the targeted cells. The catalytic activity of the expressed protein should be sufficient for activation of the prodrug. * Author to whom correspondence should be addressed. Tel: 44-181-643 8901, Fax: 44-181-770 7899 Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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Since expression of the foreign enzymes will not occur in all cells of a targeted tumour in vivo, a bystander cytotoxic effect is required whereby the prodrug is cleaved to an active drug that kills not only tumour cells but also neighbouring nonexpressing
tumour cells. This means that expression in less than 100% of tumour cells can still give total tumour cell kill. The foreign enzyme is usually expressed intracellularly (Niculescu-Duvaz et al., 1998) but by expressing the activating enzyme tethered to the outer cell surface of mammalian cells, potential advantages for GDEPT prodrug design are realised (Marais et al., 1997). Since activation in this case occurs in the interstitial spaces of the tumour, the released drug should be taken up by all cells equally, whether or not they express the activating enzyme. Thus, the bystander effect may be increased. The bacterial carboxypeptidase G2 (CPG
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