HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model

Kothari, Vishal and Joshi, Ganesh and Nama, Srikanth and Somasundaram, Kumaravel and Mulherkar, Rita (2010) HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model. In: International Journal of Cancer, 126 (3). pp. 733-742.

PDF 5.pdf - Published Version Restricted to Registered users only Download (395kB) | Request a copy

Abstract

Safety, efficacy and enhanced transgene expression are the primary concerns while using any vector for gene therapy. One of the widely used vectors in clinical. trials is adenovirus which provides a safe way to deliver the therapeutic gene. However, adenovirus has poor transduction efficiency in vivo since most tumor cells express low coxsackie and adenovirus receptors. Similarly transgene expression remains low, possibly because of the chromatization of adenoviral genome upon infection in eukaryotic cells, an effect mediated by histone deacetylases (HDACs). Using a recombinant adenovirus (Ad-HSVtk) carrying the herpes simplex thymidine kinase (HSVtk) and GFP genes we demonstrate that HDAC inhibitor valproic acid can bring about an increase in CAR expression on host cells and thereby enhanced Ad-HSVtk infectivity. It also resulted in an increase in transgene (HSVtk and GFP) expression. This, in turn, resulted in increased cell kill of HNSCC cells, following ganciclovir treatment in vitro as well as in vivo in a xenograft nude mouse model.

Item Type:	Journal Article
Publication:	International Journal of Cancer
Publisher:	john wiley and sons
Additional Information:	Copyright for this article belongs to john wiley and sons.
Keywords:	cancer gene therapy; adenoviral vector; prodrug activation; HDAC inhibitors; valproic acid
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	02 Feb 2010 07:20
Last Modified:	19 Sep 2010 05:54
URI:	http://eprints.iisc.ac.in/id/eprint/25486

Actions (login required)

View Item