HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model.
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.
Kothari
Vishal
V
Department of Genetic Engineering Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.
Joshi
Ganesh
G
Nama
Srikanth
S
Somasundaram
Kumaravel
K
Mulherkar
Rita
R
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D024201:Bystander Effect; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000821:virology; D003131:Combined Modality Therapy; D003673:Defective Viruses / Q000235:genetics; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000493:pharmacokinetics; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D056572:Histone Deacetylase Inhibitors; D011355:Prodrugs; D014635:Valproic Acid; D013937:Thymidine Kinase; D015774:Ganciclovir