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- Title
Utilization of variant-type of human α-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma.
- Authors
Ishikawa, H; Nakata, K; Mawatari, F; Ueki, T; Tsuruta, S; Ido, A; Nakao, K; Kato, Y; Ishii, N; Eguchi, K
- Abstract
We previously reported that the retroviral vector (LNAFW0.3TK) expressing the herpes simplex thymidine kinase (HSVtk) gene under the control of the 0.3 kb human α-fetoprotein (AFP) promoter provided the ganciclovir (GCV)-mediated cytotoxicity in the high AFP-producing (HuH-7) but not in the low AFP-producing (huH-1/cl.2) human hepatoma cells. In the present study, we constructed the retroviral vector (LNAFM0.3TK) in which the HSVtk gene expression is regulated by the variant-type of the 0.3 kb human AFP promoter with a G-to-A substitution at nucleotide -119, a point mutation responsible for hereditary persistence of human AFP and the vector was applied to three human hepatoma cell lines, HuH-7, huH-1/cl.2 and intermediate AFP-producing cells (PLC/PRF/5). By the reporter gene transfection assay, the activity of the variant-type of the promoter was much higher than that of the wild-type of the promoter in both HuH-7 and huH-1/cl.2 cells. Consistent with this, LNAFM0.3TK infection could sensitize huH-1/cl.2 cells, as well as HuH-7 and PLC/PRF/5 cells to GCV, but did not affect cell growth of nonhepatoma cells (HeLa). In addition, the bystander effect was achieved more efficiently by LNAFM0.3TK infection than LNAFW0.3TK infection in HuH-7 cells. These results suggest that the variant-type of the human AFP promoter ensures the therapeutic gene expression in gene therapy particularly for the low AFP-producing hepatoma cells.
- Subjects
RETROVIRUSES; GENETIC vectors; GENE expression; PROTEIN kinases; HERPES simplex virus
- Publication
Gene Therapy, 1999, Vol 6, Issue 4, p465
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3300870