Potential triple helix-mediated inhibition of IGF-I gene expression significantly reduces tumorigenicity of glioblastoma in an animal model

Cancer Gene Ther. Mar-Apr 1997;4(2):105-12.

Abstract

Oligonucleotide-directed triple helix formation is a powerful approach to block transcription of specific genes. Although the oligonucleotide triplex approach is efficient for inhibiting gene expression in cultured cells, suppression is transient. We developed an approach which inhibits insulin-like growth factor-I (IGF-I) expression following stable transfection of C6 rat glioblastoma cells with a plasmid from which an RNA is transcribed that codes for the third strand of a potential triple helix. We tested the ability of this expression vector to inhibit IGF-I gene expression in vitro as well as tumorigenesis in an animal. A dramatic reduction of IGF-I RNA and protein levels in cultured cells occurred following transfection of rat C6 cells with a eukaryotic expression plasmid encoding the oligopurine variant of the triple helix but not the oligopyrimidine or a control sequence. The cells transfected with the oligopurine variant displayed morphological changes, upregulation of major histocompatibility complex I, and increased expression of protease nexin I. Dramatic inhibition of tumor growth occurred in nude mice following injection of transfected C6 cells. To our knowledge, this is the first example of tumor growth inhibition in an animal model employing a triple helix approach.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid beta-Protein Precursor
  • Animals
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genetic Therapy / methods
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Histocompatibility Antigens Class I / drug effects
  • Histocompatibility Antigens Class I / metabolism
  • Insulin-Like Growth Factor I / chemistry
  • Insulin-Like Growth Factor I / drug effects
  • Insulin-Like Growth Factor I / genetics*
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Nucleic Acid Conformation
  • Oligonucleotides / chemistry*
  • Oligonucleotides / pharmacology*
  • Plasmids / chemistry
  • Plasmids / genetics
  • Protease Nexins
  • Protein Biosynthesis
  • Rats
  • Receptors, Cell Surface
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • Amyloid beta-Protein Precursor
  • Carrier Proteins
  • Histocompatibility Antigens Class I
  • Oligonucleotides
  • Protease Nexins
  • Receptors, Cell Surface
  • Insulin-Like Growth Factor I