Gene-Directed Enzyme Prodrug Therapy (GDEPT) of Cancer

Abstract

A new gene therapy approach for targeting cancer cells and making them sensitive to prodrugs has been proposed for human gene therapy trials (Hart and Vile, 1995; Oldfield et al., 1993). Prodrug gene therapy, commonly referred to as VDEPT (virus-directed enzyme prodrug therapy) or gene-directed enzyme prodrug therapy (GDEPT) is based on the premise that a large therapeutic benefit can be gained by transferring a drug susceptibility gene into tumor cells. The gene encodes an enzyme that catalyzes the activation of ‘a prodrug to its cytotoxic form (Fig. 1) and has been termed a “suicide gene” (Consalvo et al., 1995; Freemen et al., 1996; Mullen, 1994; Mullen et al., 1994). However, in contrast to cytotoxic gene therapy approaches that involve expression of a toxic product [for example, diphtheria toxin (Cook et al., 1994; Maxwell et al., 1991, 1992; Robinson and Maxwell, 1995)], the enzyme itself is not toxic. Thus, in GDEPT, cytotoxicity results only after administering the prodrug. There is also a bystander effect because the active drug can migrate into nontransduced cells.