title: Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Armstrong
authors.forename: Julia
authors.initials: J
authors.lastname: Davydova
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.forename: Joohee
authors.initials: J
authors.lastname: Han
authors.forename: Masato
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D014779:Virus Replication / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016898:Interferon-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human