Regulatory sequences of H19 and IGF2 genes in DNA-based therapy of colorectal rat liver metastases

Patricia Ohana*, Pinhas Schachter, Basim Ayesh, Aya Mizrahi, Tatiana Birman, Tamar Scheneider, Imad Matouk, Suhail Ayesh, Peter J.K. Kuppen, Nathan de Groot, Abraham Czerniak, Abraham Hockberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)366-374
Number of pages9
JournalJournal of Gene Medicine
Volume7
Issue number3
DOIs
StatePublished - Mar 2005
Externally publishedYes

Keywords

  • CC531 colon carcinoma cells
  • DNA-based therapy
  • DT-A gene
  • H19 gene
  • IGF2 gene
  • Liver metastases

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