In vivo gene therapy for α-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine deaminase gene

• Published in: Cancer research (Chicago, Ill.) Vol. 57; no. 3; pp. 461 - 465
• Main Authors: KANAI, F, LAN, K.-H, TAMAOKI, T, OMATA, M, SHIRATORI, Y, TANAKA, T, OHASHI, M, OKUDAIRA, T, YOSHIDA, Y, WAKIMOTO, H, HAMADA, H, NAKABAYASHI, H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.1997
• Subjects: Adenoviridae - genetics; adenovirus; alpha-Fetoproteins - biosynthesis; Animals; Antineoplastic agents; Biological and medical sciences; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - therapy; Chemotherapy; Cytosine Deaminase; Genetic Therapy; Humans; Liver Neoplasms - enzymology; Liver Neoplasms - therapy; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Nucleoside Deaminases - genetics; Pharmacology. Drug treatments; Tumor Cells, Cultured; Antineoplastic agent; Adenoviridae; Cytosine deaminase; Hepatic disease; Hepatocellular carcinoma; Established cell line; Recombinant protein; Tumor cell; Fluorouracil; Human; Enzyme; Fluoropyrimidine derivatives; Rodentia; Malignant tumor; Gene expression; α-Fetoprotein; In vitro; Genetic transfer; Virus; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Digestive diseases; Hydrolases; Gene therapy
• ISSN: 0008-5472; 1538-7445

The alpha-fetoprotein (AFP) gene is normally expressed in fetal liver and is transcriptionally silent in adult liver but overexpressed in human hepatocellular carcinoma (HCC). Here, we demonstrate that replication defective recombinant adenoviral vectors, containing the human AFP promoter/enhancer, can be used to express the Escherichia coli cytosine deaminase (CD) gene (AdAFPCD) and the beta-galactosidase gene (AdAF-PlacZ) in AFP-producing HCC cell lines. Expression of the CD gene by adenovirus from the AFP promoter/enhancer (AdAFPCD) induced cells sensitive to 5-fluorocytosine (5FC) in the AFP-producing cells but not in the AFP-nonproducing cells. Transduction by an adenoviral vector harboring an ubiquitous strong promoter and CD gene showed enzymatic activity and 5FC killing in all cell lines. When AdAFPlacZ was injected into the s.c. established hepatoma in vivo, expression of the beta-galactosidase gene was confined to AFP-producing HCC xenografts. Moreover, HCC xenografts regressed by transduction with AdAFPCD and subsequently with 5FC treatment in vivo. These findings suggest that utilization of the AFP promoter/enhancer in an adenoviral vector can confer selective expression of a heterologous suicide gene in hepatocellular carcinoma cells in vitro and in vivo.