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Adenovirus-mediated FLT1-targeted proapoptotic gene therapy of human prostate cancer

Sergey A Kaliberov1, Lyudmila N Kaliberova, Cecil R Stockard

  • 1Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|November 27, 2004
PubMed

Insights

This study developed an adenoviral vector delivering the TRAIL gene, targeting prostate cancer cells. Combining this gene therapy with radiation significantly suppressed tumor growth in mice, offering a promising new treatment strategy.

Area of Science:

  • Oncology
  • Gene Therapy
  • Cancer Biology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumor cell apoptosis, making it a therapeutic target for prostate cancer.
  • Adenoviral vectors offer efficient gene transfer, potentially overcoming limitations of recombinant TRAIL.
  • Vascular endothelial growth factor receptor FLT-1 is implicated in prostate cancer angiogenesis, growth, and metastasis, with expression in tumor endothelial and cancer cells.

Purpose of the Study:

  • To develop a targeted adenoviral vector expressing TRAIL under the FLT1 promoter (AdFlt-TRAIL) for prostate cancer therapy.
  • To evaluate the efficacy of AdFlt-TRAIL, alone and in combination with radiation, against prostate cancer.
  • To assess the in vivo therapeutic potential of AdFlt-TRAIL and radiotherapy in prostate tumor xenografts.

Main Methods:

  • Construction of an adenoviral vector (AdFlt-TRAIL) with TRAIL gene expression regulated by the FLT1 promoter.
  • In vitro assessment of AdFlt-TRAIL-induced cell death in endothelial and prostate cancer cells.
  • In vivo studies using DU145 human prostate tumor xenografts in athymic nude mice, evaluating AdFlt-TRAIL combined with ionizing radiation.

Main Results:

  • AdFlt-TRAIL effectively induced death in endothelial and prostate cancer cells.
  • The combination of AdFlt-TRAIL and ionizing radiation overcame TRAIL resistance in human prostate cancer cells.
  • In vivo treatment with AdFlt-TRAIL and radiation significantly suppressed DU145 xenograft tumor growth.

Conclusions:

  • Targeted TRAIL delivery via the FLT1 promoter using adenoviral vectors is effective in inhibiting prostate tumor growth.
  • Combination of radiotherapy and gene therapy with AdFlt-TRAIL presents a promising strategy for prostate cancer treatment.
  • This approach demonstrates the advantage of combining gene therapy with radiation for enhanced anti-cancer effects.

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