In situ use of suicide genes for therapy of brain tumours

Suicide gene therapy represents a new therapeutic approach to the treatment of patients with otherwise incurable malignant brain tumours. This strateg y involves the introduction of a gene that renders the tumour cell suscepti ble to an otherwise nontoxic prodrug. The most often used genetic prodrug a ctivation 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 a lso that responses are observed only in very small brain tumours, indicatin g insufficient vector distribution and very low transduction efficiency wit h replication-deficient vector systems. To improve treatment efficacy, the use of replication-competent oncolytic vectors in combination with new or i mproved prodrug-suicide gene systems as a part of a multimodal approach is warranted. In the context of replication-competent vectors, suicide genes m ight also be used as fail-safe genes in the case of runaway infection.