Abstract
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.
Overview summary
Tumor growth and metastasis depend on angiogenesis. The present study showed that endothelial cell-specific growth suppression is possible by transduction of the suicidal gene driven by a promoter sequence of the von Willebrand factor gene, which is widely expressed in many endothelial cells. This strategy is expected to kill the proliferating endothelial cells preferentially and may lead to inhibition of tumor angiogenesis, growth, and metastasis in vivo.
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