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Gene therapy for hepatocellular carcinoma using non-viral vectors composed of bis guanidinium-tren-cholesterol and plasmids encoding the tissue inhibitors of metalloproteinases TIMP-2 and TIMP-3.

Abstract
Metalloproteinases (MMPs) and their natural inhibitors (TIMPs) contribute to the regulation of tumor microenvironment. Their expressions are deregulated in almost all human cancers. We report a novel approach to gene therapy of hepatocellular carcinoma (HCC), using repeated injections of DNA plasmids encoding the tissue inhibitors of metalloproteinases (TIMPs) TIMP-2 or TIMP-3, and a novel competent formulation of gene transfer based on nontoxic cationic cholesterol derivatives. The new gene delivery system was efficient in demonstrating the antitumor efficiency of TIMP-2 or TIMP-3 in inhibiting tumor growth of human HuH7 HCC cells xenografted into nude mice. We show, for the first time, an in vivo effect of TIMP-3 in delaying HCC tumor growth. No treatment-related toxicity was noted. An inhibition of angiogenesis and tumor necrosis accompanied the inhibitory effects of TIMP-2 or TIMP-3 on tumor expansion and invasion. We also report a bystander effect produced by transfected HuH7 tumor cells mixed with untransfected cells in 1:1 ratio in culture that resulted in killing 98% of cells within 96 h. In addition, the soluble forms of TIMP-2 and TIMP-3 expressed by transfected cells exerted a cytotoxic effect on untransfected HuH7 cell cultures. Taken together, these results demonstrate the potential efficacy of repeated treatment of secreted TIMP-2 and TIMP-3 for the design of nonviral gene therapy for hepatocarcinoma.
AuthorsPhuong-Lan Tran, Jean-Pierre Vigneron, David Pericat, Sylvie Dubois, Dominique Cazals, Martial Hervy, Yves A DeClerck, Claude Degott, Christian Auclair
JournalCancer gene therapy (Cancer Gene Ther) Vol. 10 Issue 6 Pg. 435-44 (Jun 2003) ISSN: 0929-1903 [Print] England
PMID12768188 (Publication Type: Journal Article)
Chemical References
  • 3-((N',N'-diguanidinoethylaminoethyl)carbamoyl)cholesterol
  • Antigens, CD34
  • Cations
  • Guanidines
  • Tissue Inhibitor of Metalloproteinase-3
  • Tissue Inhibitor of Metalloproteinase-2
  • DNA
  • Cholesterol
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
Topics
  • Animals
  • Antigens, CD34 (biosynthesis)
  • Carcinoma, Hepatocellular (therapy)
  • Cations
  • Cell Line
  • Cell Line, Tumor
  • Cholesterol (analogs & derivatives, chemistry, metabolism)
  • DNA (metabolism)
  • Female
  • Gene Transfer Techniques
  • Genetic Therapy (methods)
  • Genetic Vectors
  • Guanidines (chemistry)
  • Humans
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Kinetics
  • Liver Neoplasms (therapy)
  • Matrix Metalloproteinase 2 (metabolism)
  • Matrix Metalloproteinase 9 (metabolism)
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Plasmids (metabolism)
  • Time Factors
  • Tissue Inhibitor of Metalloproteinase-2 (genetics)
  • Tissue Inhibitor of Metalloproteinase-3 (genetics)
  • Transfection

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