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Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy
- Source :
- Surgery. 152:114-122
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- Background Combination therapy with interferon alpha (IFN) is correlated with improved survival in patients with pancreatic ductal adenocarcinoma (PDAc) but frequently presents side effects. We designed a novel targeted adenovirus with replication restricted to cyclooxygenase 2 (Cox2)-overexpressing PDAcs and hypothesize that the locally delivered therapeutic gene IFN can augment oncolytic effects while minimizing systemic toxicity. Methods IFN-expressing vectors were tested in vitro with the use of 4 PDAc cell lines with cytocidal effect measured by crystal violet and colorimetrically and IFN production assayed by ELISA. Cox2 promoter activity was checked by a luciferase reporter assay. In vivo, subcutaneous tumor xenografts with 2 PDAc cell lines in nude mice were treated with a single intratumoral viral dose. Results All PDAc cell lines were Cox2-positive. Oncolysis from the novel Cox2-controlled virus was comparable or superior to Adwt, the wild-type virus without safety features. The absence of cytocidal effect in Cox2-negative cells with the novel virus indicated cancer specificity. In vivo, stronger tumor suppression from the novel virus was seen when compared with nonreplicating IFN-expressing vectors. Conclusion We demonstrated the potent therapeutic effects of a novel tumor-specific conditionally replicative IFN-expressing adenovirus. With potential to locally deliver IFN and avoid systemic toxicity, this strategy may therefore expand the application of this robust and promising therapy.
- Subjects :
- Combination therapy
Mice, Nude
Alpha interferon
Adenocarcinoma
In Vitro Techniques
Virus Replication
medicine.disease_cause
Article
Virus
Adenoviridae
Mice
Cell Line, Tumor
Pancreatic cancer
medicine
Animals
Humans
business.industry
Interferon-alpha
Cancer
Genetic Therapy
medicine.disease
Xenograft Model Antitumor Assays
Virology
Oncolytic virus
Pancreatic Neoplasms
Disease Models, Animal
Treatment Outcome
Viral replication
Cyclooxygenase 2
Cancer research
Female
Surgery
business
Carcinoma, Pancreatic Ductal
Subjects
Details
- ISSN :
- 00396060
- Volume :
- 152
- Database :
- OpenAIRE
- Journal :
- Surgery
- Accession number :
- edsair.doi.dedup.....fef97f73accd783d0091a0a97bc911ef