title: Regulatory sequences of H19 and IGF2 genes in DNA-based therapy of colorectal rat liver metastases.
abstract: BACKGROUND
  Malignant tumors of the liver are among the most common causes of cancer-related death throughout the world. Current therapeutic approaches fail to control the disease in most cases. This study seeks to explore the potential utility of transcriptional regulatory sequences of the H19 and insulin growth factor 2 (IGF2) genes for directing tumor-selective expression of a toxin gene (A fragment of diphtheria toxin), delivered by non-viral vectors.
  
  
  METHODS
  The therapeutic potential of the toxin vectors driven by the H19 and the IGF2-P3 regulatory sequences was tested in a metastatic model of rat CC531 colon carcinoma in liver.
  
  
  RESULTS
  Intratumoral injection of these vectors into colon tumors implanted in the liver of rats induced an 88% and a 50% decrease respectively in the median tumor volume as compared with the control groups. This therapeutic action was accompanied by increased necrosis of the tumor. Importantly, no signs of toxicity were detected in healthy animals after their treatment by the toxin expression vectors.
  
  
  CONCLUSIONS
  DT-A was preferentially expressed in liver metastases after being transfected with H19 or IGF2-P3 promoter-driven DT-A expression plasmids, causing a very significant inhibition of tumor growth as a result of its cytotoxic effect. Our findings strongly support the feasibility of our proposed therapeutic strategy, which may contribute to open new gene therapeutic options for human liver metastases.
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. pohana@huji.ac.il
authors.forename: Patricia
authors.initials: P
authors.lastname: Ohana
authors.forename: Pinhas
authors.initials: P
authors.lastname: Schachter
authors.forename: Basim
authors.initials: B
authors.lastname: Ayesh
authors.forename: Aya
authors.initials: A
authors.lastname: Mizrahi
authors.forename: Tatiana
authors.initials: T
authors.lastname: Birman
authors.forename: Tamar
authors.initials: T
authors.lastname: Schneider
authors.forename: Imad
authors.initials: I
authors.lastname: Matouk
authors.forename: Suhail
authors.initials: S
authors.lastname: Ayesh
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: Nathan
authors.initials: N
authors.lastname: de Groot
authors.forename: Abraham
authors.initials: A
authors.lastname: Czerniak
authors.forename: Abraham
authors.initials: A
authors.lastname: Hochberg
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007335:Insulin-Like Growth Factor II; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008297:Male; D009362:Neoplasm Metastasis; D011506:Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D015203:Reproducibility of Results
chemical_list: C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II; D004247:DNA