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Influence of the bystander effect on HSV-tk/GCV gene therapy. A review
Ingrid J van Dillen1, Nanno H Mulder, Willem Vaalburg
1Department of Medical Oncology, Groningen University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands.
Abstract:
Despite the development of new therapeutic strategies, cancer remains incurable in most patients with advanced disease. A recent potential improvement in therapeutic strategies is the concept of suicide gene therapy. After transfection with a suicide gene, cells can convert a harmless prodrug into its toxic metabolite, resulting in selective elimination of these cells. One of the most frequently studied therapeutic strategies is based on transfection with the herpes simplex virus thymidine kinase gene (HSV-tk), followed by ganciclovir administration. Despite promising results in vitro and in vivo, the antitumor effect in clinical trials remains poor, due to very low transfection efficiency. However, high percentages of transfected cells are not mandatory for complete eradication of a tumor in vivo. Transfected tumor cells appear to be capable of inducing the death of neighboring untransfected cells. This cell kill is called the "bystander effect". Various attempts have been made to increase this effect. A substantial bystander effect could overcome the limitations of low transfection efficiency and result in an enhanced and possibly clinically worthwhile antitumor effect in patients. This review is focused on the HSV-tk/GCV system and gives an overview of current knowledge on the bystander effect in vitro and in vivo. In addition, theories concerning its mechanisms and possible approaches to augment this effect are discussed. Finally, we give an overview of clinical trials using suicide gene therapy.
Insights
Suicide gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene shows promise for cancer treatment. Enhancing the bystander effect, where treated cells kill nearby cancer cells, could improve clinical outcomes.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Advanced cancer remains largely incurable despite novel therapeutic strategies.
- Suicide gene therapy offers a potential approach by selectively eliminating cancer cells.
- The herpes simplex virus thymidine kinase (HSV-tk) gene system with ganciclovir is a prominent strategy.
Purpose of the Study:
- To review the current knowledge on the bystander effect in HSV-tk/ganciclovir suicide gene therapy.
- To discuss the mechanisms underlying the bystander effect and strategies to augment it.
- To provide an overview of clinical trials utilizing suicide gene therapy.
Main Methods:
- Review of in vitro and in vivo studies on the HSV-tk/ganciclovir system.
- Analysis of theoretical mechanisms of the bystander effect.
- Compilation of data from clinical trials involving suicide gene therapy.
Main Results:
- Low transfection efficiency limits the clinical efficacy of HSV-tk suicide gene therapy.
- The bystander effect, where transfected cells induce death in neighboring untransfected cells, is crucial for tumor eradication.
- Augmenting the bystander effect may overcome limitations of low transfection rates.
Conclusions:
- The bystander effect is a key mechanism for enhancing the antitumor efficacy of HSV-tk suicide gene therapy.
- Further research into augmenting this effect is essential for clinical translation.
- Optimizing suicide gene therapy holds potential for improved cancer treatment outcomes.