Influence of the bystander effect on HSV-tk/GCV gene therapy. A review.

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.