Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type E1a and induction of TNF-α

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 ve...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2004-10, Vol.328 (1), p.52-61
Main Authors: Engler, Heidrun, Machemer, Todd, Philopena, Jennifer, Wen, Shu-Fen, Quijano, Erlinda, Ramachandra, Murali, Tsai, Van, Ralston, Robert
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenovirus
Adenovirus E1A Proteins - analysis
Adenovirus E1A Proteins - genetics
Adenovirus E1A Proteins - metabolism
Alanine Transaminase - blood
Animals
DNA, Viral - analysis
DNA, Viral - biosynthesis
Female
Genetic Vectors - genetics
Genetic Vectors - pharmacokinetics
Genetic Vectors - physiology
Hepatitis - metabolism
Hepatitis - pathology
Hepatitis - virology
Hepatotoxicity
Immunocompromised Host
Injections, Intravenous
Liver - metabolism
Liver - pathology
Liver - virology
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, SCID
Models, Animal
Mutation
Species Specificity
Time Factors
Tumor cells
Tumor Necrosis Factor-alpha - analysis
Tumor Necrosis Factor-alpha - biosynthesis
Viruses - genetics
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Summary: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-α 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-α release and E1a-mediated sensitization of hepatocyte killing.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2004.06.043