A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma.
Transducing and distributing a vector throughout a tumor mass are presently insufficient for effective cancer gene therapy. To overcome these difficulties an adenoviral vector was designed that would replicate specifically in tumor cells. This tumor-specific replication-restricted adenoviral (TSRRA) vector was constructed by requiring that the essential E1A gene be expressed from a tumor-specific promoter, namely, the alpha-fetoprotein (AFP) gene promoter. This promoter was chosen since the AFP gene is highly expressed in 70-80% of patients with hepatocellular carcinoma (HCC) but not in normal adults. HCC is one of the major worldwide causes of cancer death. A vector was constructed (AvE1a04i) and demonstrated to replicate in human AFP-producing HCC cell lines. However, little replication was observed in seven other, non-AFP-producing human cell lines, as well as primary cultures of normal human lung epithelial and endothelial cells. In addition, AvE1a04i was shown to prevent tumor growth of an ex vivo-transduced AFP-expressing HCC cell line but not a non-AFP-expressing cell line. Finally, in situ administration of AvE1a04i into preestablished tumors resulted in a greater than 50% long-term survival rate. This novel TSRRA vector for HCC demonstrated both specificity and efficacy in vitro and in vivo.
Hallenbeck
P L
PL
Genetic Therapy, a Novartis Company, Gaithersburg, MD 20878, USA.
Chang
Y N
YN
Hay
C
C
Golightly
D
D
Stewart
D
D
Lin
J
J
Phipps
S
S
Chiang
Y L
YL
D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D000509:alpha-Fetoproteins / Q000235:genetics*
D000509:alpha-Fetoproteins