Delayed morbidity and mortality of albumin/SV40 T-antigen transgenic mice after insertion of an alpha-fetoprotein/herpes virus thymidine kinase transgene and treatment with ganciclovir.
The alpha-fetoprotein (AFP) gene is normally expressed in fetal liver and transcriptionally silent in adult tissues, but can be abnormally reactivated in hepatocellular carcinoma (HCC). We linked 7.6 kb of 5'-flanking DNA from the mouse AFP gene to the herpes simplex virus (HSV) thymidine kinase gene (tk), and a line of transgenic mice was produced that expressed TK in a pattern similar to endogenous AFP. When these AFP/tk transgenic mice were crossed to another transgenic line that develops multifocal HCC due to expression of a SV40 large T-antigen transgene under regulation of the albumin promoter/enhancer complex, a significant delay of tumor progression could be achieved by administration of ganciclovir (GCV), a cytotoxic compound that is a substrate for phosphorylation by viral, but not mammalian, TK. Control animals carrying only the tk gene were unaffected by GCV treatment. These results illustrate the feasibility of prophylactic gene therapy for ablation of cancer, utilizing a strategy in which the tk gene is regulated by a promoter expected to be active only in tumor cells.
Macri
P
P
Department of Obs/Gyn & Reproductive Science, Mt. Sinai School of Medicine, New York, NY 10029.
Gordon
J W
JW
D000418:Albumins / Q000235:genetics*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005813:Genes, Synthetic; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000633:toxicity; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D000509:alpha-Fetoproteins / Q000096:biosynthesis* / Q000235:genetics
D000418:Albumins; D000952:Antigens, Polyomavirus Transforming; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D000509:alpha-Fetoproteins; D013937:Thymidine Kinase; D015774:Ganciclovir