title: Systemic gene-directed enzyme prodrug therapy of hepatocellular carcinoma using a targeted adenovirus armed with carboxypeptidase G2.
abstract: Hepatocellular carcinoma is the fifth most common cancer worldwide, and there is no effective therapy for unresectable disease. We have developed a targeted systemic therapy for hepatocellular carcinoma. The gene for a foreign enzyme is selectively expressed in the tumor cells and a nontoxic prodrug is then given, which is activated to a potent cytotoxic drug by the tumor-localized enzyme. This approach is termed gene-directed enzyme prodrug therapy (GDEPT). Adenoviruses have been used to target cancer cells, have an intrinsic tropism for liver, and are efficient gene vectors. Oncolytic adenoviruses produce clinical benefits, particularly in combination with conventional anticancer agents and are well tolerated. We rationalized that such adenoviruses, if their expression were restricted to telomerase-positive cancer cells, would make excellent gene vectors for GDEPT therapy of hepatocellular carcinoma. Here we use an oncolytic adenovirus to deliver the prodrug-activating enzyme carboxypeptidase G2 (CPG2) to tumors in a single systemic administration. The adenovirus replicated and produced high levels of CPG2 in two different hepatocellular carcinoma xenografts (Hep3B and HepG2) but not other tissues. GDEPT enhanced the adenovirus-alone therapy to elicit tumor regressions in the hepatocellular carcinoma models. This is the first time that CPG2 has been targeted and expressed intracellularly to effect significant therapy, showing that the combined approach holds enormous potential as a tumor-selective therapy for the systemic treatment of hepatocellular carcinoma.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom.
authors.forename: Silke
authors.initials: S
authors.lastname: Schepelmann
authors.forename: Paul
authors.initials: P
authors.lastname: Hallenbeck
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: Carl
authors.initials: C
authors.lastname: Hay
authors.forename: Lynda K
authors.initials: LK
authors.lastname: Hawkins
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D011623:gamma-Glutamyl Hydrolase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C097602:ZD 2767; D019098:Telomerase; D011623:gamma-Glutamyl Hydrolase