Selective destruction of gliomas in immunocompetent rats by thymidine kinase-defective herpes simplex virus type 1.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Jia
W W
WW
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
McDermott
M
M
Goldie
J
J
Cynader
M
M
Tan
J
J
Tufaro
F
F
D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D005910:Glioma / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D007121:Immunocompetence; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase