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Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment

Hanna M Leinonen1, Anna-Kaisa Ruotsalainen, Ann-Marie Määttä

  • 1Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FIN-70210 Kuopio, Finland.

Cancer Research
|October 9, 2012
PubMed

Insights

Lung cancer cells with activated Nrf2 (Nuclear factor erythroid-2 related factor 2) can be targeted for suicide gene therapy. This approach uses a vector regulated by the antioxidant response element (ARE) to deliver herpes simplex virus thymidine kinase (HSV-TK/GCV).

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Nuclear factor erythroid-2 related factor 2 (Nrf2) is crucial for cellular defense against toxins, including chemotherapy drugs.
  • Mutations in Nrf2 or Keap1 lead to constitutive Nrf2 activation and chemoresistance in many lung cancers.
  • This constitutive activation presents a potential therapeutic vulnerability in lung adenocarcinoma.

Purpose of the Study:

  • To investigate the efficacy of exploiting constitutive Nrf2 activation for lung cancer suicide gene therapy.
  • To evaluate a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under antioxidant response element (ARE) regulation.

Main Methods:

  • Utilized a lentiviral vector (LV-ARE-TK/GCV) where HSV-TK/GCV expression is controlled by the Nrf2-binding ARE.
  • Assessed ARE activity in human lung adenocarcinoma cells with constitutive Nrf2 overexpression.
  • Compared the efficacy of LV-ARE-TK/GCV with a control vector (LV-PGK-TK/GCV) in a mouse xenograft model of lung cancer.

Main Results:

  • Human lung adenocarcinoma cells with high Nrf2 showed high basal ARE activity.
  • LV-ARE-TK/GCV demonstrated superior efficacy compared to a constitutively active promoter-driven vector in these cells.
  • Suicide gene therapy with LV-ARE-TK/GCV significantly reduced tumor size in a mouse xenograft model.

Conclusions:

  • Antioxidant response element (ARE)-regulated HSV-TK/GCV suicide gene therapy is a promising strategy for lung cancer.
  • This approach effectively targets cancer cells with high constitutive ARE activity.
  • The therapy allows for enhanced therapeutic targeting of specific cancer cells, improving treatment precision.

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