The equine herpes virus 4 thymidine kinase is a better suicide gene than the human herpes virus 1 thymidine kinase.
Abstract: The herpes simplex virus type 1 thymidine kinase suicide gene (HSV1tk) together with ganciclovir (GCV) have been successfully used for in vivo treatment of various experimental tumors, and many clinical trials using this system have been launched. With the aim to improve this therapeutic system, we compared the potential efficacy of different herpes virus derived thymidine kinases (HSV1, varicella-zoster virus, equine herpes virus type-4 and Epstein-Barr virus) as suicide genes in association with the nucleoside analogs acyclovir, ganciclovir and bromovinyldeoxyur- idine. Using various murine and human cell lines expressing these viral tk, we show that HSV1- and EHV4tk are the more efficient suicide genes for the different nucleoside analogs tested. Moreover, EHV4tk expressing murine and human cells were three- to 12-fold more sensitive to GCV than HSV1tk expressing cells. This was correlated with the presence of five-fold higher amounts of the toxic triphosphated-GCV in EHV4- versus HSV1tk expressing cells. Altogether, these experiments underline the potential advantages of the EHV4tk as a suicide gene.
Publication Date: 1999-09-22 PubMed ID: 10490775DOI: 10.1038/sj.gt.3300993Google Scholar: Lookup
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- Comparative Study
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research investigated different herpes virus-derived thymidine kinases for their potential use in suicide gene therapy, concluding that the equine herpes virus type-4 thymidine kinase (EHV4tk) may work more efficiently than the commonly used human herpes virus 1 thymidine kinase (HSV1tk).
Overview of the Study
- The study looked at various thymidine kinase enzymes derived from different types of the herpes virus. These included HSV1, varicella-zoster virus, Epstein-Barr virus, and equine herpes virus type-4.
- The use of these viral thymidine kinases was studied in combination with nucleoside analogs such as acyclovir, ganciclovir, and bromovinyldeoxyuridine. The aim was to determine which combination would offer the most effective way to kill cancerous cells in suicide gene therapy.
Findings of the Study
- The researchers found that HSV1- and EHV4tk were the most effective suicide genes when used with different nucleoside analogs.
- Particularly, cells expressing EHV4tk were three to twelve times more sensitive to GCV than those expressing HSV1tk. This suggests the potential for a higher rate of cell death and, therefore, a more effective therapeutic result.
- It was also found that there were five times the amount of toxic triphosphated-GCV in cells expressing EHV4tk than those expressing HSV1tk. This supports the idea that EHV4tk may cause a higher level of cell death than HSV1tk.
Implications of the Research
- The findings of this study highlight the potential improvement in suicide gene therapy with the use of EHV4tk as a suicide gene as opposed to the currently used HSV1tk.
- The higher sensitivity to GCV and larger amounts of toxic triphosphated-GCV in EHV4tk expressing cells suggest potential for increased efficacy of gene therapy treatments.
- This research paves the way for further studies on the practical application of this treatment in clinical trials, and its potential use in treating various types of cancer.
Cite This Article
APA
Loubière L, Tiraby M, Cazaux C, Brisson E, Grisoni M, Zhao-Emonet J, Tiraby G, Klatzmann D.
(1999).
The equine herpes virus 4 thymidine kinase is a better suicide gene than the human herpes virus 1 thymidine kinase.
Gene Ther, 6(9), 1638-1642.
https://doi.org/10.1038/sj.gt.3300993 Publication
Researcher Affiliations
- Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, UPMC, CNRS ESA 7087, CERVI, Hôpital de la Pitié, 83, Boulevard de l'Hôpital, 75651 Paris cedex 13, France.
MeSH Terms
- Animals
- Antiviral Agents / therapeutic use
- Cell Line
- Ganciclovir / therapeutic use
- Gene Transfer Techniques
- Genetic Therapy / methods
- Herpesvirus 1, Human / enzymology
- Humans
- Mice
- Sensitivity and Specificity
- Thymidine Kinase / genetics
- Varicellovirus / enzymology
Citations
This article has been cited 6 times.- Qiu Z, Harms JS, Zhu J, Splitter GA. Bovine herpesvirus tegument protein VP22 enhances thymidine kinase/ganciclovir suicide gene therapy for neuroblastomas compared to herpes simplex virus VP22.. J Virol 2004 Apr;78(8):4224-33.
- Feng WH, Hong G, Delecluse HJ, Kenney SC. Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas.. J Virol 2004 Feb;78(4):1893-902.
- Wu CC, Chen MC, Chang YR, Hsu TY, Chen JY. Identification and characterization of the conserved nucleoside-binding sites in the Epstein-Barr virus thymidine kinase.. Biochem J 2004 May 1;379(Pt 3):795-803.
- Feng WH, Westphal E, Mauser A, Raab-Traub N, Gulley ML, Busson P, Kenney SC. Use of adenovirus vectors expressing Epstein-Barr virus (EBV) immediate-early protein BZLF1 or BRLF1 to treat EBV-positive tumors.. J Virol 2002 Nov;76(21):10951-9.
- Knecht W, Sandrini MP, Johansson K, Eklund H, Munch-Petersen B, Piskur J. A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines.. EMBO J 2002 Apr 2;21(7):1873-80.
- Moore SM, Cannon JS, Tanhehco YC, Hamzeh FM, Ambinder RF. Induction of Epstein-Barr virus kinases to sensitize tumor cells to nucleoside analogues.. Antimicrob Agents Chemother 2001 Jul;45(7):2082-91.
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