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.
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.
Takahashi
Minoru
M
Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, 060-8543, Japan.
Sato
Tsutomu
T
Sagawa
Tamotsu
T
Lu
Yue
Y
Sato
Yasushi
Y
Iyama
Satoshi
S
Yamada
Yasuyuki
Y
Fukaura
Junki
J
Takahashi
Sho
S
Miyanishi
Koji
K
Yamashita
Toshiharu
T
Sasaki
Katsunori
K
Kogawa
Katsuhisa
K
Hamada
Hirofumi
H
Kato
Junji
J
Niitsu
Yoshiro
Y
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000628:therapy*; D002470:Cell Survival / Q000502:physiology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003588:Cytopathogenic Effect, Viral; D017931:DNA Primers / Q000737:chemistry; D003673:Defective Viruses / Q000235:genetics / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D000509:alpha-Fetoproteins / Q000235:genetics* / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D017931:DNA Primers; D000509:alpha-Fetoproteins