We have designed a targeted systemic suicide gene therapy that combines the advantages of
tumor-selective gene expression, using the human
telomerase promoter (hTERT), with the beneficial effects of an oncolytic adenovirus to deliver the gene for the
prodrug-activating
enzyme carboxypeptidase G2 (CPG2) to
tumors. Following delivery of the vector (AdV.hTERT-CPG2) and expression of CPG2 in
cancer cells, the
prodrug ZD2767P was administered for conversion by CPG2 to a cytotoxic drug. This system is sometimes termed gene-directed
enzyme prodrug therapy (GDEPT). Here, we have shown that it is applicable to 10 human
colorectal carcinoma cell lines with a direct correlation between viral toxicity and CPG2 production. SW620 xenografts were selected for analysis and were significantly reduced or eradicated after a single administration of AdV.hTERT-CPG2 followed by a
prodrug course. The oncolytic effect of adenovirus alone did not result in
DNA cross-links or apoptosis, whereas
DNA cross-links and apoptosis occurred following
prodrug administration, showing the combined beneficial effects of the GDEPT system. The apoptotic regions extended beyond the areas of CPG2 expression in the
tumors, indicative of significant bystander effects in vivo. Higher concentrations of vector particles and CPG2 were found in the AdV.hTERT-CPG2 plus
prodrug-treated
tumors compared with the virus alone, showing an unexpected beneficial and cooperative effect between the vector and GDEPT. This is the first time that a
tumor-selective GDEPT vector has been shown to be effective in
colorectal carcinoma and that apoptosis and significant bystander effects have been identified as the mechanisms of cytotoxicity within the
tumor.