Cell-specific Cre-mediated activation of the diphtheria toxin gene in pituitary tumor cells: Potential for cytotoxic gene therapy

Eun Jig Lee, J. Larry Jameson

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Diphtheria toxin has been suggested for the treatment of malignant cancer. In this paper, we describe a strategy for targeting the expression of the diphtheria toxin gene to growth hormone (GH)-producing pituitary tumor cells using adenoviral vectors. We generated adenoviral vectors in which a stuffer DNA fragment, flanked by two loxP sequences, was placed between the GH or cytomegalovirus (CMV) promoters and the diphtheria toxin gene (GH-loxP-DT, and CMV-loxP-DT) or the β-Gal gene (GH-loxP-Gal, and CMV-loxP-Gal). Coinfection of GH-loxP-DT with either CMV-Cre or GH-Cre induced cytotoxicity that was limited to GH4 cells. Little or no cytopathic effect was seen in GH4 cells infected with control viruses (CMV-loxP-Gal or GH-loxP-Gal with CMV-Cre or GH-Cre). To test the effectiveness of this strategy in vivo, GH4 cells were transplanted into nude mice. Intratumoral co-injection of adenoviruses carrying diphtheria toxin (GH-loxP-DT, and CMV-loxP-DT) and Cre recombinase (GH-Cre, and CMV-Cre) caused rapid regression of the transplanted GH4 tumors. These results indicate that Cre-mediated activation of a loxP-repressed form of the DT gene provides a useful strategy for targeted suicide gene therapy. This approach may be useful for GH-secreting adenomas and should be applicable to other neoplastic disorders.

Original languageEnglish
Pages (from-to)533-542
Number of pages10
JournalHuman Gene Therapy
Volume13
Issue number4
DOIs
Publication statusPublished - 2002 Apr 6

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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