Imaging techniques provide a method for non-invasive longitudinal monitoring of cancer therapies, but common metrics such as tumour size are late markers and do not indicate heterogeneity of response. Apoptotic cell death is an earlier marker of tumour response and produces molecular and cellular-level changes (macromolecular breakdown, membrane changes and cell shrinkage) that may be detectable by magnetic resonance imaging (MRI). Previous studies using conventional MRI methods have shown little sensitivity to apoptosis. In this thesis it is hypothesized that, using an extracellular contrast agent to affect the MRI property of relaxation for extracellular water preferentially, parameters related to water in the intracellular and extracellular environments and the exchange between them can be obtained and will be sensitive to apoptosis. It is also hypothesized that membrane changes and macromolecular breakdown are detectable by the technique of magnetization transfer. Measurements of relaxation in the presence of contrast agent in vitro demonstrated a decrease in extracellular water fraction and an increase in the rate of water exchange across the plasma membrane during apoptosis. In vivo, this method was complicated by the difficulty of delivering contrast agent to the tumour, but regions with good delivery showed correlation between high water exchange rates from MRI and apoptosis in histology. Magnetization transfer studies indicated only small changes in vitro during apoptosis and these were largely related to changes in the free water, so this method was not investigated further. Further work is required to determine the tumour lines where the water exchange methods may be applied reliably. Nevertheless, the method of measuring water exchange presented in this thesis can be performed in a clinically-feasible amount of time (~20 minutes). It therefore has potential in detecting apoptosis and predicting therapy response. It also emphasizes the role of water exchange in conventional MRI relaxation experiments.

Imaging techniques provide a method for non-invasive longitudinal monitoring of cancer therapies, but common metrics such as tumour size are late markers and do not indicate heterogeneity of response. Apoptotic cell death is an earlier marker of tumour response and produces molecular and cellular-level changes (macromolecular breakdown, membrane changes and cell shrinkage) that may be detectable by magnetic resonance imaging (MRI). Previous studies using conventional MRI methods have shown little sensitivity to apoptosis. In this thesis it is hypothesized that, using an extracellular contrast agent to affect the MRI property of relaxation for extracellular water preferentially, parameters related to water in the intracellular and extracellular environments and the exchange between them can be obtained and will be sensitive to apoptosis. It is also hypothesized that membrane changes and macromolecular breakdown are detectable by the technique of magnetization transfer. Measurements of relaxation in the presence of contrast agent in vitro demonstrated a decrease in extracellular water fraction and an increase in the rate of water exchange across the plasma membrane during apoptosis. In vivo, this method was complicated by the difficulty of delivering contrast agent to the tumour, but regions with good delivery showed correlation between high water exchange rates from MRI and apoptosis in histology. Magnetization transfer studies indicated only small changes in vitro during apoptosis and these were largely related to changes in the free water, so this method was not investigated further. Further work is required to determine the tumour lines where the water exchange methods may be applied reliably. Nevertheless, the method of measuring water exchange presented in this thesis can be performed in a clinically-feasible amount of time (~20 minutes). It therefore has potential in detecting apoptosis and predicting therapy response. It also emphasizes the role of water exchange in conventional MRI relaxation experiments.