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Radioresponsive tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy for malignant brain

H Tsurushima1, X Yuan, L E Dillehay

  • 1Department of Biomedical Engineering, Medical School, Johns Hopkins University, Baltimore, MD, USA. hideo-tsurushima@aist.go.jp

Cancer Gene Therapy
|June 2, 2007
PubMed

Insights

This study introduces a novel radioresponsive gene therapy combining tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and radiation treatment (RT) for malignant gliomas. This approach demonstrated synergistic cell death and significant tumor volume reduction in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Malignant gliomas have a poor prognosis, necessitating novel therapeutic strategies.
  • Current treatments often lack specificity and efficacy.
  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy.

Purpose of the Study:

  • To develop and evaluate a novel radioresponsive gene therapy for malignant gliomas.
  • To combine TRAIL gene therapy with radiation treatment (RT) for synergistic effects.
  • To investigate the potential of a radioinducible promoter system for controlled gene delivery.

Main Methods:

  • Construction of a plasmid (pE4-TRAIL) with a radioinducible Egr-1 promoter driving TRAIL expression.
  • In vitro evaluation of pE4-TRAIL in U251 and U87 glioma cells, assessing apoptosis and cell killing activities.
  • In vivo transfection of pE4-TRAIL into subcutaneous U251 glioma cells in nude mice using electroporation, followed by RT.
  • Assessment of tumor apoptosis and volume changes in treated mice.

Main Results:

  • pE4-TRAIL demonstrated radioresponsive apoptosis and synergistic cell killing when combined with RT in vitro.
  • Radiation treatment influenced the expression of TRAIL death receptors, particularly in wild-type p53 glioma cells.
  • In vivo, combined pE4-TRAIL and RT treatment led to detected apoptosis and significantly reduced tumor volumes compared to control groups (P<0.001).

Conclusions:

  • Radioresponsive gene therapy, combining TRAIL and RT, shows significant potential for treating malignant gliomas.
  • This therapeutic system offers spatial and temporal control via external RT, enhancing specificity and safety.
  • The findings support further development of this targeted gene therapy approach for brain tumors.

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