Tuberc Respir Dis > Volume 45(3); 1998 > Article
Tuberculosis and Respiratory Diseases 1998;45(3):587-595.
DOI: https://doi.org/10.4046/trd.1998.45.3.587    Published online June 1, 1998.
Effect of Butyrate on Adenovirus-Mediated Herpes Simplex Virus Thymidine Kinase Gene Therapy.
Jae Yong Park, Jeong Ran Kim, Hee Jin Chang, Chang Ho Kim, Jae Ho Park, Tae Hoon Jung
1Department of Internal Medicine, Kungpook National University Hospital, Taegu, Korea.
2Cancer Research Institute, Kungpook National University Hospital, Taegu, Korea.
3Department of Internal Medicine, Keimyung University, School of Medicine, Taegu, Korea.
Abstract
BACKGROUND
Recombinant adenovirus hold promise as vectors to carry therapeutic genes for several reasons: 1) they can infect both dividing and non-dividing cells ; 2) they have the ability to directly transduce tissues in vivo; 3) they can easily be produced in high titer ; and 4) they have an established record of safety as vaccination material. However, one of the major limitation in the use of adenoviruses is that transgene expression is quite short because adenovirusees insert their DNA genome episomally rather than by chromosomal integration, and an immune response against the virus destroys cells expressing the therapeutic gene. Since sodium butyrate has been reported to induce adenovirus-mediated gene expression, we hypothesized that treatment of tumor cells, transduced with herpes simples virus thymidine kinase(HSVtk) gene using adenoviral vector, with butyrate could augment the effect of gene therapy. METHODS: We transduced HSVtk gene, driven by the cytomegalovirus promoter, into REN cell line(human mesothelioma cell line). Before proceeding with the comparison of HSVtk/ganciclovir mediated bystander killing, we evaluated the effect of butyrate on the growth of tumor cells in order to rule out a potential antitumor effect of butyrate alone, and also on expression of HSVtk gene by Western blot analysis. Then we determined the effects of butyrate on bystander-mediated cell killing in vitro. RESULTS: There was no inhibition of growth of cells exposed to butyrate for 24 hours at a concentration of 1.5mM/L. Toxic effects were seen when the concentration of butyrate was greater than 2.0mM/h Gene expression was more stable and bystander effect was augmented by butyrate treatment of a concentration of 1.5mM CONCLUSION: These results provide evidence that butyrate can augment the efficiency of cell killing with HSVtk/GCV system by inducing transgene expression and may thus by a promising new approach to improve responses in gene therapy using adenoviral vectors.
Key Words: Butyrate, Adenovirus, Gene therapy


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