Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostate-specific antigen promoter-driven DT-A adenoviral-mediated gene transfer (original) (raw)

Diphtheria toxin (DT) is a potent inhibitor of protein synthesis. As little asa single molecule of DT can result in cell-cycle independent cell death. This profound potency has led to difficulties in the development of DT as a suicide gene in cancer gene therapy, because toxicity appears to be related primarily to the fidelity of basal gene expression and the yield of viral titer. We evaluated the feasibility of prostate-specific DT gene therapy by cloning the catalytic domain (A chain) of DT under the control of the prostate-specific antigen (PSA) promoter, the PSA promoter and enhancer, or the cytomegalovirus promoter. The data on expression of DT from the plasmid constructs demonstrate that the basal level of DT gene expression determines the toxicity. To better test the potential therapeutic efficacy of DT suicide gene therapy, we first developed a DT-resistant adenoviral packaging line (293DTR). This allowed us to manufacture a relatively high titer adenoviral vector encoding t...