We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Tumor-specific activity of cellular regulatory elements is down-regulated upon insertion into the herpes simplex virus genome.
- Authors
Glaβ, Mandy; Söling, Ariane; Messerle, Martin
- Abstract
Transcriptional targeting of viral genes is a promising strategy to achieve tumor-specific replication of oncolytic viruses. Due to its natural tropism, herpes simplex virus type 1 (HSV-1) may be an ideal tool for oncolytic therapy of brain tumors such as malignant glioblastoma. To study whether gliomaspecific gene expression can be accomplished within the HSV-1 genome, four cellular regulatory elements were exemplarily studied. Whereas the human telomerase reverse transcriptase (hTERT) and survivin promoters and the nestin and vascular endothelial growth factor A (VEGF-A) enhancers displayed pronounced glioma specificity after plasmid transfection, only the nestin enhancer conferred a certain selectivity for glioma cells and notable activity when transferred into the viral genome. The nestin enhancer was also found to be highly useful for tumor cell-specific expression of a therapeutically relevant gene (interleukin-2) when tested in combination with the hTERT or simian virus 40 (SV40) early promoter in the HSV-1 genome. Because activity of the chosen promoter in a tumor is a prerequisite for the successful application of an oncolytic virus, we examined whether the activity of a promoter can be deduced from the amounts of cellular mRNA or protein expressed under its control. We found little correlation between promoter activity and mRNA levels of the corresponding gene, whereas protein expression was more closely related to promoter activity. We conclude that the cellular elements are differently regulated in the viral and cellular genomes. Mechanistic insight into the differential regulation is required to improve and refine the design of transcriptionally targeted HSV vectors.
- Subjects
CELLULAR control mechanisms; HERPES simplex virus; VIRAL genetics; CANCER cells; GENE targeting; GENETIC transcription; GENE expression
- Publication
Journal of NeuroVirology, 2008, Vol 14, Issue 6, p522
- ISSN
1355-0284
- Publication type
Article
- DOI
10.1080/13550280802348214