E1B-55K-deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capable of highly specific replication in AFP-producing hepatocellular carcinoma and eradication of established tumor

Minoru Takahashi; Tsutomu Sato; Tamotsu Sagawa; Yue Lu; Yasushi Sato; Satoshi Iyama; Yasuyuki Yamada; Junki Fukaura; Sho Takahashi; Koji Miyanishi; Toshiharu Yamashita; Katsunori Sasaki; Katsuhisa Kogawa; Hirofumi Hamada; Junji Kato; Yoshiro Niitsu

doi:10.1006/mthe.2002.0589

E1B-55K-deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capable of highly specific replication in AFP-producing hepatocellular carcinoma and eradication of established tumor

Mol Ther. 2002 May;5(5 Pt 1):627-34. doi: 10.1006/mthe.2002.0589.

Authors

Minoru Takahashi¹, Tsutomu Sato, Tamotsu Sagawa, Yue Lu, Yasushi Sato, Satoshi Iyama, Yasuyuki Yamada, Junki Fukaura, Sho Takahashi, Koji Miyanishi, Toshiharu Yamashita, Katsunori Sasaki, Katsuhisa Kogawa, Hirofumi Hamada, Junji Kato, Yoshiro Niitsu

Affiliation

¹ Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, 060-8543, Japan.

PMID: 11991754
DOI: 10.1006/mthe.2002.0589

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

Adenovirus E1A Proteins / genetics
Adenovirus E1A Proteins / metabolism*
Adenovirus E1B Proteins / genetics
Adenovirus E1B Proteins / metabolism*
Adenoviruses, Human / genetics
Adenoviruses, Human / physiology
Animals
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / therapy*
Cell Survival / physiology
Colon / metabolism
Colon / pathology
Cytopathogenic Effect, Viral
DNA Primers / chemistry
Defective Viruses / genetics
Defective Viruses / physiology
Enhancer Elements, Genetic
Female
Genetic Therapy / methods*
Genetic Vectors / genetics
Genetic Vectors / physiology
Hepatocytes / metabolism
Hepatocytes / virology
Humans
Liver Neoplasms, Experimental / metabolism
Liver Neoplasms, Experimental / therapy*
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation
Plasmids
Polymerase Chain Reaction
Promoter Regions, Genetic
Tumor Cells, Cultured
Virus Replication
alpha-Fetoproteins / genetics*
alpha-Fetoproteins / metabolism*

Substances

Adenovirus E1A Proteins
Adenovirus E1B Proteins
DNA Primers
alpha-Fetoproteins