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Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas

Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas
Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas
Malignant gliomas are the most common primary brain tumors in adults and, with few exceptions, have a dismal prognosis despite the therapeutic use of surgery, radiation therapy, and chemotherapy. Because CNS gliomas rarely metastasize, they represent an attractive target for gene therapy through local gene delivery. Here we report on the use of two different fusogenic membrane glycoproteins (FMGs), the measles virus proteins F and H (MV-F and MV-H) and a mutated form of the retroviral envelope protein of the gibbon ape leukemia virus (GALV.fus), as a novel class of therapeutic transgenes in gliomas. Transfection of U87 and U118 cells with MV-F and MV-H cDNA or GALV.fus cDNA led in 48 hr to massive syncytial formation followed by cell death. FMG-mediated cytotoxicity in the U87 and U118 cell lines was superior to the cytotoxicity caused by transfection with HSV-tk cDNA followed by ganciclovir (GCV) treatment at all time points. At high-density cell seeding, addition of tumor cells transfected with MV-F and H killed at least 1 log more cells than by HSV-tk + GCV treatment, indicating higher bystander effect. Similar results were obtained with GALV.fus. The mechanism of syncytial death in cultured glioma cell lines was predominantly apoptotic. Transfection of U87 cells with F + H or GALV.fus expression constructs completely suppressed their tumorigenicity. Treatment of established U87 xenografts in nude mice with a combination of F and H adenoviruses at 1:1 ratio led to complete tumor regression, significantly higher antitumor effect, and prolongation of survival as compared with control animals treated with a GFP adenovirus. In summary, the viral fusogenic membrane glycoproteins (GALV and the MV-F + MV-H combination) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas.
1043-0342
811-821
Galanis, Evanthia
b1217b8e-2d25-43be-adaf-5b8001c74b56
Bateman, Andrew
a851558d-8b9b-4020-b148-a239c2b26815
Johnson, Kimberly
4e5ebb62-ae59-429f-94bd-202af5e5cebd
Diaz, Rosa M.
f52592cc-dadb-4ac4-8d8e-03505c305b34
James, C. David
3f8ec05b-0abf-45a8-a66f-eaf9b6fef361
Vile, Richard
a2252a95-3f21-447f-ab45-c7fcc888151f
Russell, Stephen J.
9e0e141c-4cfe-452f-b672-e6232fb95d1f
Galanis, Evanthia
b1217b8e-2d25-43be-adaf-5b8001c74b56
Bateman, Andrew
a851558d-8b9b-4020-b148-a239c2b26815
Johnson, Kimberly
4e5ebb62-ae59-429f-94bd-202af5e5cebd
Diaz, Rosa M.
f52592cc-dadb-4ac4-8d8e-03505c305b34
James, C. David
3f8ec05b-0abf-45a8-a66f-eaf9b6fef361
Vile, Richard
a2252a95-3f21-447f-ab45-c7fcc888151f
Russell, Stephen J.
9e0e141c-4cfe-452f-b672-e6232fb95d1f

Galanis, Evanthia, Bateman, Andrew, Johnson, Kimberly, Diaz, Rosa M., James, C. David, Vile, Richard and Russell, Stephen J. (2001) Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas. Human Gene Therapy, 12 (7), 811-821. (doi:10.1089/104303401750148766).

Record type: Article

Abstract

Malignant gliomas are the most common primary brain tumors in adults and, with few exceptions, have a dismal prognosis despite the therapeutic use of surgery, radiation therapy, and chemotherapy. Because CNS gliomas rarely metastasize, they represent an attractive target for gene therapy through local gene delivery. Here we report on the use of two different fusogenic membrane glycoproteins (FMGs), the measles virus proteins F and H (MV-F and MV-H) and a mutated form of the retroviral envelope protein of the gibbon ape leukemia virus (GALV.fus), as a novel class of therapeutic transgenes in gliomas. Transfection of U87 and U118 cells with MV-F and MV-H cDNA or GALV.fus cDNA led in 48 hr to massive syncytial formation followed by cell death. FMG-mediated cytotoxicity in the U87 and U118 cell lines was superior to the cytotoxicity caused by transfection with HSV-tk cDNA followed by ganciclovir (GCV) treatment at all time points. At high-density cell seeding, addition of tumor cells transfected with MV-F and H killed at least 1 log more cells than by HSV-tk + GCV treatment, indicating higher bystander effect. Similar results were obtained with GALV.fus. The mechanism of syncytial death in cultured glioma cell lines was predominantly apoptotic. Transfection of U87 cells with F + H or GALV.fus expression constructs completely suppressed their tumorigenicity. Treatment of established U87 xenografts in nude mice with a combination of F and H adenoviruses at 1:1 ratio led to complete tumor regression, significantly higher antitumor effect, and prolongation of survival as compared with control animals treated with a GFP adenovirus. In summary, the viral fusogenic membrane glycoproteins (GALV and the MV-F + MV-H combination) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas.

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Published date: 2001

Identifiers

Local EPrints ID: 26317
URI: http://eprints.soton.ac.uk/id/eprint/26317
ISSN: 1043-0342
PURE UUID: cd2cfd5d-6743-4e90-9c66-d292e9770d91

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Date deposited: 24 Apr 2006
Last modified: 15 Mar 2024 07:09

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Contributors

Author: Evanthia Galanis
Author: Andrew Bateman
Author: Kimberly Johnson
Author: Rosa M. Diaz
Author: C. David James
Author: Richard Vile
Author: Stephen J. Russell

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