Radiation and gene therapy: rays of hope for the new millennium?

Radiotherapy is, after surgery, the most widely used form of cancer treatment but the main limitation of radiation treatment is damage to normal tissues. This may be overcome by targeted radiotherapy - the selective delivery to malignant deposits of cytotoxic radionuclides bound to tumour-seeking agents. Several gene transfer techniques are being evaluated which combine gene therapy and targeted radiotherapy, rendering malignant cells more sensitive to radiation or causing them to take up radioactive drugs - providing tumour cell kill with reduced damage to normal tissues. This review examines several aspects of targeted radiotherapy/gene therapy strategies. As well as identification of suitable gene/radiopharmaceutical combinations, expression of the transgenes must be confined to tumour cells via tumour specific transcriptional regulation or via delivery vehicles which specifically target tumour cells. The inability of current delivery vehicles to target every cell within a tumour mass must be addressed by maximising collateral cell damage in targeted radiotherapy strategies via radiation mediated bystander effects and suitable in vitro models are described, which allow assessment of promising gene transfer strategies in scenarios where tumour heterogeneity of transgene expression and cell proliferative state are considered.