Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy

Leonard Armstrong, Amanda Arrington, Joohee Han, Tatyana Gavrikova, Eric Brown, Masato Yamamoto, Selwyn M. Vickers, Julia Davydova

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated. Methods: Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens. Results: Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown. Conclusions: Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer-specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients.

Original languageEnglish (US)
Pages (from-to)741-750
Number of pages10
JournalAmerican Journal of Surgery
Volume204
Issue number5
DOIs
StatePublished - Nov 2012

Keywords

  • Adenoviral death protein (ADP)
  • Adenovirus
  • Conditionally replicative adenovirus (CRAd)
  • Cox2
  • Gene therapy
  • Interferon-alfa
  • Krumdiek tissue slicer
  • Oncolytic virus
  • Pancreatic cancer

ASJC Scopus subject areas

  • Surgery

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