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

被引：43

作者：

Engler, H ^{[1
]}

Machemer, T ^{[1
]}

Philopena, J ^{[1
]}

Wen, SF ^{[1
]}

Quijano, E ^{[1
]}

Ramachandra, M ^{[1
]}

Tsai, V ^{[1
]}

Ralston, R ^{[1
]}

机构：

[1] Canji Inc, San Diego, CA 92121 USA

来源：

VIROLOGY | 2004年 / 328卷 / 01期

关键词：

hepatotoxicity; adenovirus; tumor cells;

D O I：

10.1016/j.virol.2004.06.043

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 (d/01/07) or a virus lacking E1a. The results suggest a mechanism for hepatotoxicity involving virus-induced production of local TNF-alpha release and El-amediated sensitization of hepatocyte killing. (C) 2004 Elsevier Inc. All rights reserved.

引用

页码：52 / 61

页数：10

共 65 条

[1] Interferon α2b gene delivery using adenoviral vector causes inhibition of tumor growth in xenograft models from a variety of cancers [J].