Suicide gene therapy of human colon carcinoma xenografts using an armed oncolytic adenovirus expressing carboxypeptidase G2.
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.
Schepelmann
Silke
S
The Institute of Cancer Research, Cancer Research UK Centres for Cancer Therapeutics, London, United Kingdom.
Ogilvie
Lesley M
LM
Hedley
Douglas
D
Friedlos
Frank
F
Martin
Janet
J
Scanlon
Ian
I
Chen
Ping
P
Marais
Richard
R
Springer
Caroline J
CJ
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
D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C097602:ZD 2767; D019098:Telomerase; D011623:gamma-Glutamyl Hydrolase