Abstract
The herpes simplex virus thymidine kinase (HSV-TK) gene is being developed in the treatment of many different types of tumors. The HSV-TK gene sensitizes tumor cells to the antiviral drug ganciclovir (GCV) and mediates the bystander effect in which unmodified tumor cells are killed as well. Although this approach has shown a significant antitumor effect, the need to potentiate this therapy exists. The results of this study indicate that recombinant interferon α2a (IFNα2a) acts synergistically with GCV to kill HSV-TK-expressing PA1 human ovarian tumor cells. Furthermore, it enhances the bystander killing of nearby unmodified tumor cells that do not express the HSV-TK gene. Previous studies have suggested that in vitro and in vivo bystander effects may be mediated by different mechanisms. However, IFNα2a enhanced bystander killing in both systems, with the survival of mice bearing preexisting tumors being significantly prolonged when they were treated with IFNα2a and HSV-TK/GCV compared with either treatment alone. Mechanism studies have shown that treatment with IFNα2a and GCV caused an increase in cells in S phase 24 hours after therapy in the HSV-TK-expressing cells, but the mechanism of action of IFNα2a does not seem to be related to an increase in DNA damage, because GCV incorporation was not increased after treatment with IFNα2a. These findings suggest that IFNα2a may be a useful adjunctive therapy for the HSV-TK/GCV system.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Whartenby, K., Darnowski, J., Freeman, S. et al. Recombinant interferon α2a synergistically enhances ganciclovir-mediated tumor cell killing in the herpes simplex virus thymidine kinase system. Cancer Gene Ther 6, 402–408 (1999). https://doi.org/10.1038/sj.cgt.7700063
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cgt.7700063
Keywords
This article is cited by
-
Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer
Cancer Gene Therapy (2006)
-
Participation of Interferon-Alpha in Regulation of Apoptosis
Journal of Evolutionary Biochemistry and Physiology (2005)
-
Herpes simplex virus thymidine kinase and granulocyte macrophage colony-stimulating factor combination gene therapy in a murine CT26 cell colon cancer model
Cancer Gene Therapy (2004)
-
A role for MAP kinase in the antitumor activity of a nucleoside analog
Cancer Gene Therapy (2002)