A Herpes Simplex Virus Type 1 Mutant with γ34.5 and LAT Deletions Effectively Oncolyses Human U87 Glioblastomas in Nude Mice

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Abstract
We previously constructed a novel recombinant herpes simplex virus with deletions in the γ34.5 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. 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. 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 mm2 (mean ± standard error), whereas the average for the DM33 group was 4.61 ± 1.57 mm2 and that for the DM33 plus ganciclovir group was 2.49 ± 1.32 mm2. 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. 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.

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