Evaluation of E1A double mutant oncolytic adenovectors in anti-glioma gene therapy.
J Med Virol
; 80(9): 1595-603, 2008 Sep.
Article
em En
| MEDLINE
| ID: mdl-18649343
ABSTRACT
Malignant glioma, in particular glioblastoma multiforme (GBM), represents one of the most devastating cancers currently known and existing treatment regimens do little to change patient prognosis. Conditionally replicating adenoviral vectors (CRAds) represent attractive experimental anti-cancer agents with potential for clinical application. However, early protein products of the wild type adenovirus backbone--such as E1A--limit CRAds' replicative specificity. In this study, we evaluated the oncolytic potency and specificity of CRAds in which p300/CPB and/or pRb binding capacities of E1A were ablated to reduce non-specific replicative cytolysis. In vitro cytopathic assays, quantitative PCR analysis, Western blot, and flow cytometry studies demonstrate the superior anti-glioma efficacy of a double-mutated CRAd, Ad2/24CMV, which harbors mutations that reduce E1A binding to p300/CPB and pRb. When compared to its single-mutated and wild type counterparts, Ad2/24CMV demonstrated attenuated replication and cytotoxicity in representative normal human brain while displaying enhanced replicative cytotoxicity in malignant glioma. These results have implications for the development of double-mutated CRAd vectors for enhanced GBM therapy.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
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Adenoviridae
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Proteínas E1A de Adenovirus
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Vírus Oncolíticos
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Terapia Viral Oncolítica
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Vetores Genéticos
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Glioma
Limite:
Humans
Idioma:
En
Revista:
J Med Virol
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos