Magnetic Resonance Imaging and the Development of Vascular Targeted Treatments for Cancer

The main subject of the work presented in this thesis is the further development of magnetic resonance imaging (MRI) as a non-invasive method of investigating tumour microcirculation. Two different MR techniques were used: dynamic contrast enhanced (DCE)-MRI and Blood Oxygen Level Dependent (BOLD)-MRI. Intravital microscopy was used to help interpret BOLD-MRI results. The ultimate aims were to determine whether MRI methods could be relied upon to define a drug as having vascular disrupting activity and to develop techniques to predict the effectiveness of vascular disruptive agents (VDA). In DCE-MRI, tissue enhancement is continuously monitored over several minutes after intravenous injection of contrast medium. Modelling of contrast agent kinetics generates quantitative parameters related to tissue blood flow rate and permeability, e.g. Ktrans (transfer constant). In a clinical study, patients had DCE-MRI examinations before and 24 hours after cytotoxic chemotherapy to establish whether any acute anti-vascular effects could be detected. No acute reductions in Ktrans were seen. In this project, the acute effects of the VDA, combretastatin A-4-phosphate, were investigated using DCE-MRI in SW1222 tumours in mice. Responses were seen both at a clinically relevant dose and at higher doses, and a dose-response relationship established. BOLD-MRI can detect changes in oxygenation and blood flow within tumours using deoxygenated haemoglobin as an intrinsic contrast agent. Tumours contain a variable proportion of immature vessels, which may explain differential sensitivity to VDAs. In this project, BOLD-MRI was used to assess tumour vessel maturity using consequent vasoreactivity to angiotensin II and carbon dioxide (as air-5%C02 or as carbogen) in an animal model. Intravital microscopy was used to directly observe response to these agents in mouse window chambers. Results suggest that response to vasoactive agents is useful for assessing vascular maturity in tumours but that more sensitive non-invasive imaging methods than BOLD-MRI are required for clinical use.