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Selective destruction of gliomas in immunocompetent rats by thymidine kinase-defective herpes simplex virus type 1
W W Jia1, M McDermott, J Goldie
1Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Background:
Thymidine kinase-deficient herpes simplex virus type 1 [tk(-) HSV-1] replicates well in dividing cells but not in nondividing cells such as neurons, suggesting a potential use in the treatment of brain tumors.
Purpose:
We attempted to examine the efficacy of using tk(-) HSV-1 for treating brain tumors in immunocompetent animals.
Methods:
9L glioma cells were cultured and subsequently implanted intracerebrally in immunocompetent, adult male Long-Evans rats. A thymidine kinase-defective HSV-1 virus, KOS-SB, was used to infect 9L cells in culture, and the viability of the infected cells was compared with that of mock-infected (i.e., uninfected) cells. We also injected the virus intratumorally and determined the mortality of the tumor-bearing animals. Tumor regression and viral spread following virus injection were examined by histologic and immunocytochemical assays.
Results:
In vitro, the tk(-) virus destroyed cultured 9L cell monolayers at multiplicities of infection of 0.1 and 1.0 within 48 hours. With the same quantity of virus, no remarkable difference in survival of neural cells was found. Foscarnet, an antiviral drug that acts independently of tk activity, blocked viral replication by greater than 99% at a concentration of 100 micrograms/mL. The mortality of animals bearing tumors declined with an increase in the amount of virus injected. Histologic examination showed that the HSV-1 treatment caused severe tumor regression. Immunocytochemistry using an anti-HSV-1 antibody revealed only a weak staining within the regressing tumors, and few immunopositive neurons were evident in the surrounding brain tissue.
Conclusions:
The results indicate that tk(-) HSV-1 mutants can selectively and effectively destroy glioma cells both in vitro and in vivo in normal, immunocompetent animals.
Implications:
Our failure to detect viral spread associated with regressing tumors suggests that some other cytopathic factors might be involved in the tumor regression. Regardless of the precise mode of tumor cell killing, HSV-1 may be useful for treating brain tumors.
Insights
Thymidine kinase-deficient herpes simplex virus type 1 (tk(-) HSV-1) effectively destroyed glioma cells in vitro and in vivo. This oncolytic virus shows promise for brain tumor treatment in immunocompetent animals.
Area of Science:
- Oncolytic virology
- Gene therapy for cancer
- Viral oncology
Background:
- Thymidine kinase-deficient herpes simplex virus type 1 (tk(-) HSV-1) selectively replicates in dividing cells.
- This characteristic suggests its potential application in targeting rapidly proliferating brain tumor cells, which are often in non-dividing neuronal environments.
Purpose of the Study:
- To evaluate the therapeutic efficacy of tk(-) HSV-1 against brain tumors in immunocompetent animal models.
- To assess the virus's selectivity and safety in normal neural tissues.
Main Methods:
- 9L glioma cells were cultured and implanted intracerebrally into Long-Evans rats.
- Cells were infected with tk(-) HSV-1 (KOS-SB) in vitro, and viability was assessed.
- Virus was injected intratumorally in tumor-bearing rats, and survival rates, tumor regression, and viral spread were analyzed via histology and immunocytochemistry.
Main Results:
- tk(-) HSV-1 demonstrated potent cytopathic effects on 9L glioma cells in vitro.
- In vivo, increased viral dosage led to reduced mortality in tumor-bearing rats, with significant tumor regression observed.
- Histology revealed minimal viral presence in surrounding neural tissues, suggesting localized action.
Conclusions:
- tk(-) HSV-1 mutants effectively and selectively eliminate glioma cells both in vitro and in vivo in immunocompetent hosts.
- The observed tumor regression may involve mechanisms beyond direct viral cytolysis, warranting further investigation.
- HSV-1 holds potential as a therapeutic agent for brain tumor treatment.
