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 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.
Wildner
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Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, USA. owildner@nhgri.nih.gov
D000256:Adenoviridae; D001932:Brain Neoplasms / Q000628:therapy*; D015774:Ganciclovir / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D006801:Humans; D011355:Prodrugs / Q000627:therapeutic use; D012328:RNA Viruses; D013937:Thymidine Kinase / Q000627:therapeutic use
D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir