Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin

Olga Greco, Tanya M. Powell, Brian Marples, Michael C. Joiner, Simon D. Scott

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Combining gene therapy with radiotherapy and chemotherapy holds potential to increase the efficacy of cancer treatment, while minimizing side effects. We tested the responsiveness of synthetic gene promoters containing CArG elements from the Early Growth Response 1 (Egr1) gene after neutron irradiation, doxorubicin and cisplatin. Human MCF-7 breast adenocarcinoma and U373-MG glioblastoma cells were transfected with plasmids containing CArG promoters controlling the expression of the green fluorescent protein (GFP). Exposing the cells to neutrons, doxorubicin or cisplatin resulted in a significant induction of transgene expression. Therapeutic advantage was demonstrated by replacing the reporter with the herpes simplex virus thymidine kinase (HSVtk), able to convert the prodrug ganciclovir (GCV) into a cytotoxin. A 1.3 Gy neutron dose caused 49% growth inhibition in MCF-7 cells, which increased to 63% in irradiated CArG-HSVtk-transfectants treated with GCV. Exposure to 0.5 μM cisplatin or 0.01 μM doxorubicin induced a growth inhibition of 25-30% in MCF-7 cells. In the presence of GCV, this value increased to 65-70% in cells transfected with the CArG promoter constructs driving the expression of HSVtk. These data indicate that combining CArG-mediated HSVtk/GCV suicide gene therapy with radio- and chemotherapy can enhance antitumor toxicity, and validates future in vivo investigations.

Original languageEnglish (US)
Pages (from-to)655-662
Number of pages8
JournalCancer Gene Therapy
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

Fingerprint

Ganciclovir
Thymidine Kinase
Neutrons
Simplexvirus
Genetic Therapy
Doxorubicin
Cisplatin
MCF-7 Cells
Growth
Genes
Radiotherapy
Synthetic Genes
Drug Therapy
Cytotoxins
Prodrugs
Glioblastoma
Green Fluorescent Proteins
Transgenes
Suicide
Adenocarcinoma

Keywords

  • Adriamycin
  • GFP
  • HSVtk/GCV
  • Radiation

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin. / Greco, Olga; Powell, Tanya M.; Marples, Brian; Joiner, Michael C.; Scott, Simon D.

In: Cancer Gene Therapy, Vol. 12, No. 7, 01.07.2005, p. 655-662.

Research output: Contribution to journalArticle

Greco, Olga ; Powell, Tanya M. ; Marples, Brian ; Joiner, Michael C. ; Scott, Simon D. / Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin. In: Cancer Gene Therapy. 2005 ; Vol. 12, No. 7. pp. 655-662.
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