Inhibition of glioma cells in vitro and in vivo using a recombinant adenoviral vector containing an astrocyte-specific promoter

Didier Vandier, Olivier Rixe, François Besnard, Min Kim, Toshiki Rikiyama, Merrill Goldsmith, Michael Brenner, Alain Gouyette, Kenneth H Cowan

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene in combination with the drug ganciclovir (GCV) is a promising approach for the treatment of cancer-inducing gliomas, a tumor with a poor prognosis. In an attempt to limit the toxic effects on normal tissues, we constructed a recombinant adenoviral vector, Adgfa2TK, in which the HSV-TK gene is driven by the promoter for the gene encoding glial fibrillary acidic protein, an intermediate filament protein expressed primarily in astrocytes. Infection by Adgfa2TK of a glial cell line (C6) and a non-glial cell line (MDA-MB-231) revealed markedly increased expression of HSV-TK in glial cells as determined by Western blot. In comparison, high HSV-TK protein levels were produced in both cell lines after infection with a control virus, AdCMVTK, in which the constitutive cytomegalovirus viral promoter was used to direct HSV-TK expression. Infection of two glial cell lines (C6, U251) and two non-glial cell lines (HepG2, MDA-MB-231) with Adgfa2TK followed by GCV treatment revealed high toxicity in glial cell lines (50% growth inhibitory concentration: <2 μg/mL of GCV) with little or no toxicity (50% growth inhibitory concentration: >75 μg/mL) in the non-glial cell lines. In vivo, injection of Adgfa2TK into C6 tumors grown in nude mice followed by intraperitoneal GCV treatment significantly repressed tumor growth compared with the controls. Adgfa2TK may be useful for directing expression of the HSV-TK gene to gliomas.

Original languageEnglish (US)
Pages (from-to)1120-1126
Number of pages7
JournalCancer Gene Therapy
Volume7
Issue number8
DOIs
Publication statusPublished - Jan 1 2000

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Keywords

  • Adenovirus
  • Gene therapy
  • Glial fibrillary acidic protein
  • Glioblastoma
  • Herpes simplex virus thymidine kinase gene

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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