Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability.

Abstract

BACKGROUND:

We have previously developed an oncolytic serotype 5 adenovirus (Ad5) with chromogranin-A (CgA) promoter-controlled E1A expression, Ad[CgA-E1A], with the intention to treat neuroendocrine tumors, including carcinoids. Since carcinoids tend to metastasize to the liver it is important to fully repress viral replication in hepatocytes to avoid adenovirus-related liver toxicity. Herein, we explore miRNA-based regulation of E1A expression as a complementary mechanism to promoter-based transcriptional control.

METHODOLOGY/PRINCIPAL FINDINGS:

Ad[CgA-E1A-miR122], where E1A expression is further controlled by six tandem repeats of the target sequence for the liver-specific miR122, was constructed and compared to Ad[CgA-E1A]. We observed E1A suppression and replication arrest of the miR122-detargeted adenovirus in normal hepatocytes, while the two viruses killed carcinoid cells to the same degree. Repeated intravenous injections of Ad[CgA-E1A] induced liver toxicity in mice while Ad[CgA-E1A-miR122] injections did not. Furthermore, a miR122-detargeted adenovirus with the wild-type E1A promoter showed reduced replication in hepatic cells compared to wild-type Ad5 but not to the same extent as the miR122-detargeted adenovirus with the neuroendocrine-selective CgA promoter.

CONCLUSIONS/SIGNIFICANCE:

A combination of transcriptional (promoter) and post-transcriptional (miRNA target) regulation to control virus replication may allow for the use of higher doses of adenovirus for efficient tumors treatment without liver toxicity.

• Authors: Justyna Leja, Berith Nilsson, Di Yu, Elisabet Gustafson, Göran Akerström, Kjell Oberg, Valeria Giandomenico, Magnus Essand
• Journal: PloS one (PLoS One) Vol. 5 Issue 1 Pg. e8916 (Jan 27 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20111709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• Models, Theoretical
• Neoplasms (drug therapy, pathology)
• Stochastic Processes