Investigating the mechanisms of α-particle therapy in prostate cancer

Abstract

The use of α-particle radionuclide emitters in the treatment of bone metastasis has been an active area of research within targeted radionuclide therapies. From a radiobiological perspective, α-particles are known to be more effective at killing cells in comparison to low linear energy transfer (LET) radiation particles, such as X-rays, with increased relative biological effectiveness of around a factor of 3 in most models. α-particle irradiated cells also show a reduced dependency on radioresistance mechanisms observed in the absence of oxygen, with an oxygen enhancement ratio (OER) close to 1.0. Such advantageous radiobiological properties of α-particles demonstrate their potential for radiotherapy treatments. In recent years, the bone targeting high LET radionuclide Radium-223 (223Ra) has been shown to not only have a palliative effect but also a survival prolonging effect in castration resistant prostate cancer patients with bone metastases. This has encouraged the use of 233Ra in more extensive clinical trials. Despite the clinical utility of 233Ra, little is known regarding the radionuclide’s mechanisms of action in this treatment setting, where accurate assessments of the dosimetry underpinning its effectiveness are lacking. There is a pressing need to model and quantify α-emitter effects in pre-clinical models so the next generation of trials utilising 223Ra can be optimally designed. The research work presented in this thesis focused on studying the dosimetry involved in α-particle irradiation systems for in vitro and clinical settings, using computational simulation methods. We have also studied the α-particle irradiation effects on cell survival, DNA damage and tumour control, focusing specifically on 223Ra treatment scenarios