Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy

Surgery. 2012 Jul;152(1):114-22. doi: 10.1016/j.surg.2012.02.017. Epub 2012 Apr 11.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy*
  • Adenoviridae* / genetics
  • Adenoviridae* / physiology
  • Animals
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / therapy*
  • Cell Line, Tumor
  • Cyclooxygenase 2 / metabolism*
  • Disease Models, Animal
  • Female
  • Genetic Therapy
  • Humans
  • In Vitro Techniques
  • Interferon-alpha / genetics
  • Interferon-alpha / therapeutic use*
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Treatment Outcome
  • Virus Replication / physiology
  • Xenograft Model Antitumor Assays

Substances

  • Interferon-alpha
  • Cyclooxygenase 2
  • PTGS2 protein, human