title: Suicide gene therapy of human colon carcinoma xenografts using an armed oncolytic adenovirus expressing carboxypeptidase G2.
abstract: 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.
authors.affiliation: The Institute of Cancer Research, Cancer Research UK Centres for Cancer Therapeutics, London, United Kingdom.
authors.forename: Silke
authors.initials: S
authors.lastname: Schepelmann
authors.forename: Lesley M
authors.initials: LM
authors.lastname: Ogilvie
authors.forename: Douglas
authors.initials: D
authors.lastname: Hedley
authors.forename: Frank
authors.initials: F
authors.lastname: Friedlos
authors.forename: Janet
authors.initials: J
authors.lastname: Martin
authors.forename: Ian
authors.initials: I
authors.lastname: Scanlon
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy* / Q000821:virology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D050130:Oncolytic Virotherapy / Q000379:methods; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D011623:gamma-Glutamyl Hydrolase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C097602:ZD 2767; D019098:Telomerase; D011623:gamma-Glutamyl Hydrolase