Use of von Willebrand factor promoter to transduce suicidal gene to human endothelial cells, HUVEC.
Angiogenesis is an essential component of multifactorial carcinogenesis and thus a potential target of therapeutic intervention. To develop a novel cancer gene therapy strategy based on suppression of tumor angiogenesis, we examined the feasibility of targeting and preferential killing of proliferating endothelial cells by use of the von Willebrand factor (vWf) promoter and herpes simplex virus thymidine kinase gene (HSV-TK). Based on previous reports on the vWf promoter, we tested two putative vWf promoter regions. The luciferase assay showed that the shorter region, which encompasses most of the first noncoding exon, had stronger activity in endothelial cells. Although the promoter activity was low when employed as an internal promoter for retroviral and adenoviral vectors, endothelial cell specificity was suggested; the promoter, when used to drive the HSV-TK gene, could preferentially suppress endothelial cell growth in the presence of prodrug ganciclovir, suggesting the feasibility of designing an anti-angiogenesis gene therapy using the vWf promoter and the suicide gene/prodrug strategy.
Ozaki
K
K
Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Yoshida
T
T
Ide
H
H
Saito
I
I
Ikeda
Y
Y
Sugimura
T
T
Terada
M
M
D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003001:Cloning, Molecular; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000378:metabolism; D015774:Ganciclovir / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic / Q000235:genetics; D014470:Umbilical Cord; D014841:von Willebrand Factor / Q000235:genetics*
D017931:DNA Primers; D014841:von Willebrand Factor; D008156:Luciferases; D013937:Thymidine Kinase; D015774:Ganciclovir