Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type E1a and induction of TNF-alpha.
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.
Engler
Heidrun
H
Canji, Inc., 3525 John Hopkins Court, San Diego, CA 92121, USA. heidrun.engler@canji.com
Machemer
Todd
T
Philopena
Jennifer
J
Wen
Shu-Fen
SF
Quijano
Erlinda
E
Ramachandra
Murali
M
Tsai
Van
V
Ralston
Robert
R
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004279:DNA, Viral / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000493:pharmacokinetics* / Q000502:physiology; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D016867:Immunocompromised Host; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D023421:Models, Animal; D009154:Mutation; D013045:Species Specificity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*; D014780:Viruses / Q000235:genetics
D017500:Adenovirus E1A Proteins; D004279:DNA, Viral; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase