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Updated: Oct 17, 2026
Modeling Brain Tumors In Vivo Using Electroporation-Based Delivery of Plasmid DNA Representing Patient Mutation Signatures
Published on: June 23, 2023
In situ use of suicide genes for therapy of brain tumours
1Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, USA. owildner@nhgri.nih.gov
Abstract:
Suicide gene therapy represents a new therapeutic approach to the treatment of patients with otherwise incurable malignant brain tumours. This strategy involves the introduction of a gene that renders the tumour cell susceptible to an otherwise nontoxic prodrug. The most often used genetic prodrug activation system is the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) paradigm. An important aspect of this system is the 'bystander effect', the extension of cytotoxic effects to untransduced cells. For gene delivery, retroviral, adenoviral vectors and HSV-1 mutants have been used. Clinical studies have revealed that the HSV-tk/GCV approach is safe, but also that responses are observed only in very small brain tumours, indicating insufficient vector distribution and very low transduction efficiency with replication-deficient vector systems. To improve treatment efficacy, the use of replication-competent oncolytic vectors in combination with new or improved prodrug-suicide gene systems as a part of a multimodal approach is warranted. In the context of replication-competent vectors, suicide genes might also be used as fail-safe genes in the case of runaway infection.
Insights
Suicide gene therapy offers a novel treatment for malignant brain tumors by making cancer cells sensitive to a prodrug. Current methods show promise but require improved vector delivery for better tumor cell targeting and efficacy.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Malignant brain tumors are often incurable with conventional therapies.
- Suicide gene therapy introduces a gene to sensitize tumor cells to a prodrug.
- The herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is a common approach.
Purpose of the Study:
- To review the current state of suicide gene therapy for malignant brain tumors.
- To identify limitations of existing gene delivery vectors and prodrug systems.
- To propose strategies for enhancing treatment efficacy.
Main Methods:
- Review of clinical studies on HSV-tk/GCV suicide gene therapy.
- Analysis of gene delivery vectors including retroviral, adenoviral, and HSV-1 mutants.
- Discussion of the 'bystander effect' in suicide gene therapy.
Main Results:
- The HSV-tk/GCV approach is safe but shows limited efficacy in larger tumors due to poor vector distribution and transduction efficiency.
- Replication-deficient vectors exhibit insufficient distribution and transduction.
- The bystander effect extends cytotoxic effects to non-transduced cells.
Conclusions:
- Improved vector systems, such as replication-competent oncolytic vectors, are needed for better treatment outcomes.
- Combination with novel prodrug-suicide gene systems in a multimodal approach is recommended.
- Suicide genes can serve as fail-safe mechanisms in replication-competent vector systems.
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