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Tumor-specific apoptotic gene targeting overcomes radiation resistance in esophageal adenocarcinoma

Joe Y Chang1, Xiaochun Zhang, Ritsuko Komaki

  • 1Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jychang@mdanderson.org

International Journal of Radiation Oncology, Biology, Physics
|April 4, 2006
PubMed
Abstract

Insights

Combining tumor-specific tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy with radiotherapy significantly enhances esophageal adenocarcinoma treatment, increasing survival and inhibiting tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Esophageal adenocarcinoma often exhibits resistance to conventional radiotherapy.
  • Targeting apoptosis pathways presents a strategy to overcome treatment resistance.

Purpose of the Study:

  • To investigate the synergistic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy combined with radiotherapy in overcoming radiation resistance in esophageal adenocarcinoma.
  • To evaluate the efficacy of a tumor-specific adenoviral vector (Ad/TRAIL-F/RGD) in sensitizing cancer cells to radiation.

Main Methods:

  • Adenoviral vector Ad/TRAIL-F/RGD, utilizing a tumor-specific promoter, was employed to deliver the TRAIL gene to esophageal adenocarcinoma cells and normal lung fibroblasts (NHLF).
  • Apoptosis induction was assessed using Western blot, flow cytometry, and TUNEL assays.
  • A mouse model of human esophageal adenocarcinoma was treated with intratumoral Ad/TRAIL-F/RGD injections alongside local radiotherapy.

Main Results:

  • The combination therapy significantly enhanced cancer cell killing compared to monotherapy, without affecting normal cells.
  • Combined treatment led to reduced clonogenic formation and increased DNA fragmentation (sub-G1 accumulation) in cancer cells.
  • Apoptosis was confirmed by the activation of key caspases (caspase-9, -8, -3) and PARP cleavage in vitro, and by TUNEL assay in vivo.
  • Tumor growth was dramatically inhibited, and mean survival was prolonged from 16.7 days (radiotherapy alone) to 31.6 days in the combination group.

Conclusions:

  • Tumor-specific TRAIL gene delivery combined with radiotherapy is an effective strategy to enhance the suppression of esophageal adenocarcinoma growth.
  • This combined approach significantly improves survival rates in preclinical models, offering a promising therapeutic avenue.

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