Systemic gene-directed enzyme prodrug therapy of hepatocellular carcinoma using a targeted adenovirus armed with carboxypeptidase G2

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2005-06, Vol.65 (12), p.5003-5008
Main Authors: SCHEPELMANN, Silke, HALLENBECK, Paul, SPRINGER, Caroline J, OGILVIE, Lesley M, HEDLEY, Douglas, FRIEDLOS, Frank, MARTIN, Janet, SCANLON, Ian, HAY, Carl, HAWKINS, Lynda K, MARAIS, Richard
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenovirus
Animals
Antineoplastic agents
Biological and medical sciences
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - therapy
Carcinoma, Hepatocellular - virology
Cell Line, Tumor
DNA-Binding Proteins
Female
gamma-Glutamyl Hydrolase - biosynthesis
gamma-Glutamyl Hydrolase - genetics
gamma-Glutamyl Hydrolase - metabolism
Gastroenterology. Liver. Pancreas. Abdomen
Genetic Therapy - methods
Humans
Liver Neoplasms - genetics
Liver Neoplasms - therapy
Liver Neoplasms - virology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mice
Mice, Nude
Nitrogen Mustard Compounds - pharmacokinetics
Nitrogen Mustard Compounds - pharmacology
Pharmacology. Drug treatments
Prodrugs - pharmacokinetics
Prodrugs - pharmacology
Promoter Regions, Genetic
Telomerase - genetics
Tumors
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-0393