Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type E1a and induction of TNF-alpha.
Virology
; 328(1): 52-61, 2004 Oct 10.
Article
em En
| MEDLINE
| ID: mdl-15380358
Replication competent adenoviruses with various E1 modifications designed to restrict their replication to tumor cells are being evaluated as oncolytic agents in clinical trials. In mouse models, we observed that such oncolytic adenoviruses showed greater hepatotoxicity than E1-deleted adenovirus vectors following intravenous administration. Additional studies in congenic BALB/c, nude, and beige/Scid mice demonstrated dose-dependent hepatotoxicity and indicated that beige/Scid was the most sensitive strain. Comparison of E1-containing viruses showed that hepatotoxicity correlated with expression of wild-type E1a in the liver. Pharmacokinetic analysis showed rapid increases in viral DNA levels in the liver with a virus containing wild-type E1a. This was correlated with rapid induction of TNF-alpha to high levels and with rapid elevation of serum ALT. Hepatotoxicity was significantly reduced for an adenovirus with deletions in the region E1a (dl01/07) or a virus lacking E1a. The results suggest a mechanism for hepatotoxicity involving virus-induced production of local TNF-alpha release and E1a-mediated sensitization of hepatocyte killing.
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Bases de dados:
MEDLINE
Assunto principal:
Adenoviridae
/
Fator de Necrose Tumoral alfa
/
Proteínas E1A de Adenovirus
/
Vetores Genéticos
/
Hepatite
/
Fígado
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Virology
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos