title: Adenovirus-mediated transcriptional targeting of colorectal cancer and effects on treatment-resistant hypoxic cells.
abstract: BACKGROUND
  Colorectal cancer is the second leading cause of cancer-related mortality and frequently presents with locally advanced or metastatic disease. Adenovirus (Ad) vectors are important gene delivery agents because they offer efficient and broad tissue transduceability. However, their ability to penetrate through multicell layers in colorectal cancers and maintain expression in colon tumor-related hypoxic conditions has yet to be analyzed. Furthermore, their broad tissue tropism presents safety concerns.
  
  
  METHODS
  An ex vivo cultured patient tumor sample model was employed to examine Ad transduction of colorectal tumors.
  
  
  RESULTS
  Results obtained from Ad delivery of the firefly luciferase (FLuc) reporter gene indicated that colon tumor tissue was more amenable to Ad transduction than other tumor histologic types examined (breast and ovary). Ad transduction levels were significantly higher than a range of viral and nonviral methods examined in patient colon tissue. Control of transgene expression using the CXC chemokine receptor 4 (CXCR4) promoter was examined as a strategy to confine expression to tumor cells. An Ad construct carrying FLuc under the control of the human CXCR4 promoter demonstrated low reporter gene expression compared with the ubiquitously expressing cytomegalovirus promoter in normal colon and liver tissue while providing high expression in tumors, demonstrating a 'tumour-on' and 'normal-off' phenotype in patient tissue. The effects of changing hypoxia on Ad-related transgene expression were examined in an in vitro model of hypoxic conditions relevant to clinical colorectal tumors. Reporter gene expression varied depending on the level of hypoxia, with significantly reduced levels observed with prolonged hypoxia. However, transgene expression was robust in the cycling hypoxic conditions relevant to colorectal tumors.
  
  
  CONCLUSIONS
  This study provides novel, clinically relevant data demonstrating the potential for efficient gene delivery to colorectal tumors using Ad.
authors: Cork Cancer Research Centre, Mercy University Hospital and Leslie C. Quick, Jr. Laboratory, University College Cork, Cork, Ireland.
authors: Simon
authors: S
authors: Rajendran
authors: Gerald C
authors: GC
authors: O'Sullivan
authors: Deirdre
authors: D
authors: O'Hanlon
authors: Mark
authors: M
authors: Tangney
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D019718:Receptors, CXCR4 / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D019718:Receptors, CXCR4
keywords: CXCR4; Gene delivery; Hypoxia; Luciferase; Tumor