In situ use of suicide genes for therapy of brain tumours

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.