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Double-detargeted o...
Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability
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- Leja, Justyna (author)
- Uppsala universitet,Enheten för klinisk immunologi,Essand
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- Nilsson, Berith (author)
- Uppsala universitet,Enheten för klinisk immunologi,Essand
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- Yu, Di (author)
- Uppsala universitet,Enheten för klinisk immunologi,Essand
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- Gustafson, Elisabet (author)
- Uppsala universitet,Barnkirurgi
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- Åkerström, Göran (author)
- Uppsala universitet,Endokrinkirurgi
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- Öberg, Kjell (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Endocrine Oncology
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- Giandomenico, Valeria (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Endocrine Oncology
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- Essand, Magnus (author)
- Uppsala universitet,Enheten för klinisk immunologi,Essand
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(creator_code:org_t)
- 2010-01-27
- 2010
- English.
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:1, s. e8916-
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Abstract
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- 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.
Keyword
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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