Marie Boyd - Overview
To date, the most promising agents for targeted radiotherapy are radiolabelled MIBG, which has provided good remissions in neuroblastoma patients and sodium radioiodide (Na131I) for the sterilisation of thyroid carcinoma. The uptake of these radionuclides is carried out actively via the Noradrenaline Transporter (NAT) and Sodium Iodide Symporter (NIS) respectively. We have shown that transfection of the NAT and NIS genes into non-NAT expressing human glioma cells, induced expression of functional transporters which facilitated active uptake of [131I]MIBG and Na131I.
This resulted in a dose-dependent toxicity to the host cells, demonstrating
- combining gene transfection with radionuclide therapy using MIBG and NaI as the molecular vehicle and
- application of [131I]MIBG and Na131I therapy for non-neural crest tumours. We will compare the cell-kill potential achieved from these systems in a range of tumour types and utilising different radionuclides including 131I and 211At.
An attractive characteristic of these strategies is an incorporated, radiological bystander effect derived from cross-fire_irradiation of non-transfected cells. We will assess the potential advantage provided by cross-fire (radiological bystander effect) between targeted and untargeted cells using our recently developed transfected mosaic spheroid model, composed of mixtures of transfected and untransfected cells.
To achieve tumour-selective expression of therapeutic transgenes different promoter elements including the RNA component (hTR) and protein component (hTERT) telomerase promoters will be assessed for their ability to regulate the transcription of NAT and NIS transgenes in tumour cells. The issue of transgene delivery is also being assessed by utilisation of a range of delivery vehicles including the attenuated HSV 1716 virus and immunoliposomes.
It is expected that these studies will enable the development of novel therapies for a range of human malignancies.
