Retrovirus-mediated gene therapy for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by human alpha-fetoprotein enhancer directly linked to its promoter.
We have previously reported that a retrovirus vector (LNAF0.3TK) carrying a herpes simplex virus thymidine kinase gene regulated only by the 0.3-kb human alpha-fetoprotein (AFP) promoter provides ganciclovir (GCV)-mediated cytotoxicity in high AFP-producing human hepatoma cells but not in low AFP-producing cells. In the present study, a retrovirus vector (LNAF0.3(E+)TK), in which herpes simplex virus thymidine kinase gene expression is under the control of a human AFP enhancer directly linked to its promoter, was constructed and compared with LNAF0.3(E+)TK. In the intermediate and low AFP-producing human hepatoma cells PLC/PRF/5 and huH1/cl.2, respectively, as well as in the high AFP-producing human hepatoma cells (HepG2), LNAF0.3(E+)TK sensitized these cells to GCV in vitro but did not affect cell growth in nonhepatoma cells (HeLa). In an animal model using athymic mice harboring PLC/PRF/5 cells, GCV treatment resulted in more pronounced growth inhibition in the LNAF0.3(E+)TK virus-infected cells than in the LNAF0.3(E+)TK virus-infected cells. These results indicate that the human AFP enhancer that is directly linked to its promoter involves selective and enhanced tumoricidal activity in gene therapy for hepatocellular carcinoma.
Mawatari
F
F
The First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Tsuruta
S
S
Ido
A
A
Ueki
T
T
Nakao
K
K
Kato
Y
Y
Tamaoki
T
T
Ishii
N
N
Nakata
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy* / Q000821:virology; D002455:Cell Division / Q000187:drug effects; D004742:Enhancer Elements, Genetic; D015774:Ganciclovir / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D008114:Liver Neoplasms, Experimental / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D012190:Retroviridae / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D000509:alpha-Fetoproteins / Q000235:genetics*
D000970:Antineoplastic Agents; D000509:alpha-Fetoproteins; D013937:Thymidine Kinase; D015774:Ganciclovir