A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice

Ken Samoto, Moneeb Ehtesham, Guey-Chuen Perng, Kazuhiro Hashizume, Steven L. Wechsler, Anthony B. Nesburn, Keith L. Black, John S. Yu, James T. Rutka, Paul L. Kornblith, Joseph M. Piepmeier, Roberta P. Glick, Terry Lichtor, Andrew T. Parsa, Jeffrey N. Bruce

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

OBJECTIVE: 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. 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 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. CONCLUSION: 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.

Original languageEnglish
Pages (from-to)599-606
Number of pages8
JournalNeurosurgery
Volume50
Issue number3
DOIs
Publication statusPublished - 2002 Mar 1

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Human Herpesvirus 1
Glioblastoma
Nude Mice
Glioma
Ganciclovir
Viruses
Neoplasms
Corpus Striatum
Virus Diseases
Simplexvirus
Therapeutics
Green Fluorescent Proteins
Cell Size
Neuroglia
Genes
Safety
Neurons
Control Groups
Injections
Survival

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Surgery

Cite this

Samoto, Ken ; Ehtesham, Moneeb ; Perng, Guey-Chuen ; Hashizume, Kazuhiro ; Wechsler, Steven L. ; Nesburn, Anthony B. ; Black, Keith L. ; Yu, John S. ; Rutka, James T. ; Kornblith, Paul L. ; Piepmeier, Joseph M. ; Glick, Roberta P. ; Lichtor, Terry ; Parsa, Andrew T. ; Bruce, Jeffrey N. / A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice. In: Neurosurgery. 2002 ; Vol. 50, No. 3. pp. 599-606.
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title = "A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice",
abstract = "OBJECTIVE: 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. 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 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. CONCLUSION: 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.",
author = "Ken Samoto and Moneeb Ehtesham and Guey-Chuen Perng and Kazuhiro Hashizume and Wechsler, {Steven L.} and Nesburn, {Anthony B.} and Black, {Keith L.} and Yu, {John S.} and Rutka, {James T.} and Kornblith, {Paul L.} and Piepmeier, {Joseph M.} and Glick, {Roberta P.} and Terry Lichtor and Parsa, {Andrew T.} and Bruce, {Jeffrey N.}",
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Samoto, K, Ehtesham, M, Perng, G-C, Hashizume, K, Wechsler, SL, Nesburn, AB, Black, KL, Yu, JS, Rutka, JT, Kornblith, PL, Piepmeier, JM, Glick, RP, Lichtor, T, Parsa, AT & Bruce, JN 2002, 'A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice', Neurosurgery, vol. 50, no. 3, pp. 599-606. https://doi.org/10.1097/00006123-200203000-00031

A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice. / Samoto, Ken; Ehtesham, Moneeb; Perng, Guey-Chuen; Hashizume, Kazuhiro; Wechsler, Steven L.; Nesburn, Anthony B.; Black, Keith L.; Yu, John S.; Rutka, James T.; Kornblith, Paul L.; Piepmeier, Joseph M.; Glick, Roberta P.; Lichtor, Terry; Parsa, Andrew T.; Bruce, Jeffrey N.

In: Neurosurgery, Vol. 50, No. 3, 01.03.2002, p. 599-606.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice

AU - Samoto, Ken

AU - Ehtesham, Moneeb

AU - Perng, Guey-Chuen

AU - Hashizume, Kazuhiro

AU - Wechsler, Steven L.

AU - Nesburn, Anthony B.

AU - Black, Keith L.

AU - Yu, John S.

AU - Rutka, James T.

AU - Kornblith, Paul L.

AU - Piepmeier, Joseph M.

AU - Glick, Roberta P.

AU - Lichtor, Terry

AU - Parsa, Andrew T.

AU - Bruce, Jeffrey N.

PY - 2002/3/1

Y1 - 2002/3/1

N2 - OBJECTIVE: 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. 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 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. CONCLUSION: 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.

AB - OBJECTIVE: 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. 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 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. CONCLUSION: 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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