当前位置： SCI文献检索 > JOURNAL OF VIROLOGY期刊下所有文献 > Linked tumor-selective virus replication and transgene expression from E3-containing oncolytic adenoviruses.

Linked tumor-selective virus replication and transgene expression from E3-containing oncolytic adenoviruses.

Abstract：

:Historically, the adenoviral E3 region was found to be nonessential for viral replication in vitro. In addition, adenoviruses whose genome was more than approximately 105% the size of the native genome were inefficiently packaged. These profound observations were used experimentally to insert transgenes into the adenoviral backbone. More recently, however, the reintroduction of the E3 region into oncolytic adenoviruses has been found to positively influence antitumor efficacy in preclinical models and clinical trials. In the studies reported here, the granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA sequence has been substituted for the E3-gp19 gene in oncolytic adenoviruses that otherwise retained the E3 region. Five viruses that differed slightly in the method of transgene insertion were generated and compared to Ar6pAE2fGmF (E2F/GM/DeltaE3), a previously described E3-deleted oncolytic adenovirus encoding GM-CSF. In all of the viruses, the human E2F-1 promoter regulated E1A expression and GM-CSF expression was under the control of the adenoviral E3 promoter and the packaging signal was relocated immediately upstream from the right terminal repeat. The E3-gp19-deleted viruses had similar cytolytic properties, as measured in vitro by cytotoxicity assays, but differed markedly in their capacity to express and secrete GM-CSF. Ar15pAE2fGmF (E2F/GM/E3b), the virus that produced the highest levels of GM-CSF and retained the native GM-CSF leader sequence, was selected for further analysis. The E2F/GM/E3b and E2F/GM/DeltaE3 viruses exhibited similar cytotoxic activity and GM-CSF production in several tumor cell lines in vitro. However, when compared in vivo in nude mouse xenograft tumor models, E2F/GM/E3b spread through tumors to a greater extent, resulted in higher peak GM-CSF and total exposure levels in both tumor and serum, and was more efficacious than the E3-deleted virus. Using the matched WI-38 (parental) and WI-38-VA13 (simian virus 40 large T antigen transformed) cell pair, GM-CSF was shown to be selectively produced in cells expressing high levels of E2F, indicating that the tumor-selective E2F promoter controlled E1A and GM-CSF expression.

journal_name

J Virol

journal_title

Journal of virology

authors

Zhu M,Bristol JA,Xie Y,Mina M,Ji H,Forry-Schaudies S,Ennist DL

doi

10.1128/JVI.79.9.5455-5465.2005

subject

Has Abstract

pub_date

2005-05-01 00:00:00

pages

5455-65

issue

eissn

0022-538X

issn

1098-5514

pii

79/9/5455

journal_volume

pub_type

杂志文章

在线工具

Linked tumor-selective virus replication and transgene expression from E3-containing oncolytic adenoviruses.