Abstract
Here, we constructed a recombinant replication-competent adenovirus (rRCAd; AdAFPep/Rep) that expresses both E1A-13S driven by the alpha-fetoprotein (AFP) enhancer/promoter (AFPep) lacking any silencers in the 5'-flanking region of the AFP gene, and 55K-deleted E1B driven by the cytomegalovirus (CMV) promoter. We then examined the feasibility of gene therapy utilizing this virus for AFP-producing hepatocellular carcinoma (HCC). AdAFPep/Rep lysed all the AFP-producing HCC cell lines (HuH7, HepG2, PLC/PRF/5 (P5)) examined at a multiplicity of infection (MOI) as low as 0.1 and did not lyse primary human hepatocytes (Hc) at a MOI as high as 100, indicating that the rRCAd virus can lyse AFP-producing HCC cells with a higher specificity and potency than previously reported. Furthermore, this virus was capable of complete eradication of a preestablished HuH7-cell tumor by a single intratumoral injection of 10(8) plaque-forming units (pfu) of AdAFPep/Rep. Thus, AdAFPep/Rep may be applicable for clinical use.
MeSH terms
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Adenovirus E1A Proteins / genetics
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Adenovirus E1A Proteins / metabolism*
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Adenovirus E1B Proteins / genetics
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Adenovirus E1B Proteins / metabolism*
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Adenoviruses, Human / genetics
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Adenoviruses, Human / physiology
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Animals
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / therapy*
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Cell Survival / physiology
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Colon / metabolism
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Colon / pathology
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Cytopathogenic Effect, Viral
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DNA Primers / chemistry
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Defective Viruses / genetics
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Defective Viruses / physiology
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Enhancer Elements, Genetic
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Female
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Genetic Therapy / methods*
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Genetic Vectors / genetics
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Genetic Vectors / physiology
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Hepatocytes / metabolism
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Hepatocytes / virology
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Humans
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / therapy*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mutation
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Plasmids
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Polymerase Chain Reaction
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Promoter Regions, Genetic
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Tumor Cells, Cultured
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Virus Replication
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alpha-Fetoproteins / genetics*
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alpha-Fetoproteins / metabolism*
Substances
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Adenovirus E1A Proteins
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Adenovirus E1B Proteins
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DNA Primers
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alpha-Fetoproteins