Radiation physics and genetic targeting: new directions for radiotherapy. The Douglas Lea Lecture 1999.

Radiation as a cancer treatment modality is of high physical precision but limited biological specificity. Targeted radiotherapy, the delivery of radiation to cancer cells by radioisotopes conjugated to tumour-seeking targeting agents, is a biologically attractive option but is currently effective for just a few tumour types (neuroblastoma, lymphoma) for which efficacious targeting agents are available. Radiobiological modelling and radiation microdosimetry have provided useful guidelines in choosing treatment strategies for targeted radiotherapy. These considerations generally favour the incorporation of targeted radiotherapy as one component of a multimodal treatment regimen. Very recently, gene therapy techniques have been developed which should enhance the clinical efficacy of both external beam radiation and targeted radiotherapy. Typically, non-harmful viruses are modified to incorporate therapeutic genes which cause altered cellular radiosensitivity or which facilitate the cellular uptake of targeting agents. To achieve specificity, therapeutic genes would be co-transfected with tissue-specific promoter genes causing the therapeutic genes to be expressed in cells of particular types. In laboratory models, our research group are exploring the transfection-mediated uptake of the targeting agents MIBG and sodium iodide. These approaches do not require transfection of every cell in order to cure a tumour-cells which have escaped transfection may be sterilized by radiation cross-fire from transfected neighbours. A new task for radiation microdosimetry is to quantify the cross-fire effect and to compute the efficacies of gene transfection which will be required for tumour cure. In the spirit of Douglas Lea, the analytic approach of physics can be used to illuminate and enhance developments in genetics, to the benefit of medicine.