A herpes simplex virus type 1 mutant with gamma 34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice.
OBJECTIVE
We previously constructed a novel recombinant herpes simplex virus with deletions in the gamma 34.5 and LAT genes. LAT was replaced by the gene for green fluorescent protein, to allow monitoring of viral transduction in vitro and in vivo. We previously confirmed that this virus, designated DM33, retains its oncolytic properties in vitro and is inhibited with respect to spontaneous reactivation. The objective of this study was to demonstrate the therapeutic efficiency of this virus in the treatment of human gliomas in nude mice.


METHODS
Thirty BALB/c nude mice underwent stereotactic implantation of U-87 MG gliomas in the right corpus striatum. Subsequently, mice received intratumoral inoculations of either DM33 (n = 20) or virus-free medium (n = 10). Ten mice given injections of DM33 were also treated intraperitoneally with ganciclovir.


RESULTS
Intratumoral administration of DM33 to nude mice bearing intracranial U-87 MG human gliomas prolonged survival times, compared with saline-treated control animals (P < 0.05). Histological analyses of treated tumors demonstrated decreased tumor size and tumor cell lysis. Control tumors averaged 7.05 +/- 0.83 mm(2) (mean +/- standard error), whereas the average for the DM33 group was 4.61 +/- 1.57 mm(2) and that for the DM33 plus ganciclovir group was 2.49 +/- 1.32 mm(2). The difference in tumor sizes between the control group and the DM33 plus ganciclovir group was statistically significant (P = 0.044). Viral infection was limited to the tumors, and replication was not observed in normal neurons or glia.


CONCLUSIONS
The efficacy of this virus in the treatment of experimental gliomas, its safety (as confirmed by its inability to reactivate), and its attenuated neurovirulence make DM33 a promising oncolytic agent for glioma therapy.
Samoto
Ken
K
Maxine Dunitz Neurosurgical Institute, Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.
Ehtesham
Moneeb
M
Perng
Guey-Chuen
GC
Hashizume
Kazuhiro
K
Wechsler
Steven L
SL
Nesburn
Anthony B
AB
Black
Keith L
KL
Yu
John S
JS
D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D003342:Corpus Striatum; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000627:therapeutic use; D017353:Gene Deletion; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy / Q000821:virology*; D049452:Green Fluorescent Proteins; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D007202:Indicators and Reagents; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D008164:Luminescent Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D014764:Viral Proteins / Q000235:genetics*; D014780:Viruses / Q000235:genetics*
D000998:Antiviral Agents; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D049452:Green Fluorescent Proteins; D015774:Ganciclovir