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Related Experiment Videos

Hypoxia-mediated tumour targeting.

K Binley1, Z Askham, L Martin

  • 1Oxford BioMedica (UK) Ltd, Medawar Centre, Oxford Science Park, Oxford, UK.

Gene Therapy
|March 21, 2003
PubMed
Summary
This summary is machine-generated.

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This study developed a hypoxia-responsive promoter (OBHRE) for targeted gene expression in tumors. The OBHRE promoter effectively controlled gene expression in vivo, enhancing cancer gene therapy safety and efficacy.

Area of Science:

  • Oncolytic Virotherapy
  • Molecular Oncology
  • Gene Therapy

Background:

  • Tumor hypoxia is a hallmark of cancer, activating hypoxia-inducible factor 1 (HIF-1).
  • HIF-1 regulates genes with hypoxia-response elements (HREs), offering a target for cancer therapy.
  • Adenovirus vectors are utilized for in vivo gene delivery.

Purpose of the Study:

  • To evaluate an optimized hypoxia-responsive promoter (OBHRE) for in vivo gene expression using an adenovirus vector.
  • To assess the therapeutic potential of OBHRE-driven gene expression in a tumor microenvironment.
  • To investigate the ability of OBHRE to mitigate adenovirus-mediated hepatotoxicity.

Main Methods:

  • Constructed an adenovirus vector with an OBHRE driving expression of therapeutic genes.

Related Experiment Videos

  • Assessed promoter activity in liver, spleen, and tumor tissues in vivo.
  • Evaluated tumor growth delay using an adenovirus expressing cytochrome P450 (CYP2B6) under OBHRE control with cyclophosphamide (CPA).
  • Investigated hepatotoxicity using a thymidine kinase (TK) expressing adenovirus under OBHRE control with ganciclovir (GCV).

    • Main Results:

    • OBHRE demonstrated significantly lower activity in liver/spleen compared to CMV/IE promoter but comparable activity within the tumor microenvironment.
    • Adenovirus expressing CYP2B6 under OBHRE control effectively delayed tumor growth in response to CPA.
    • Adenovirus expressing TK under OBHRE control (Ad.HRETK) was well-tolerated, unlike Ad.CMVTK, which caused significant liver necrosis with GCV treatment.

    Conclusions:

    • Hypoxia-targeted gene expression via the OBHRE promoter is feasible and effective in vivo.
    • OBHRE enables selective gene expression within the tumor microenvironment, sparing healthy tissues.
    • This approach enhances the therapeutic window for cytotoxic cancer gene therapy, reducing on-target toxicity.