Developing and applying pre-clinical tumour models in order to determine the mechanistic action of applied therapies is essential if we aim to improve antitumour strategies in the clinical setting. The chaotic nature of tumour vasculature impacts directly on the effectiveness of combined chemo-radiotherapy and antiangiogenic (AA) strategies and as such warrants closer study. This work looked at the effects of novel AAs combined with clinically relevant radiotherapy (RT) using both conventional murine xenograft growth delay studies and real-time imaging. The imaging methodology was the non-invasive Dorsal Window Chamber/Intra Vital Microscopy (DWC/IVM) model which allows the study of real-time vascular responses to these therapies. The DWC/IVM model was applied to determine whether the DNA repair inhibitors Nicotinamide, AG14361 and AGO14699 had additional modes of action which could contribute to tumour radioresistance/radiosensitivity. Using the DWC/IVM model a secondary quantifiable mechanistic function was determined where these drugs also increased tumour vessel permeability. The DWC/IVM model was also used to investigate the effects of AZD2171 and AZD6244 combined with radiotherapy. These agents can inhibit angiogenic signalling pathways and it was demonstrated that both drugs worked by reducing tumour microvascular density when used in combination with radiation. In studies looking at the influence of hypoxia inducible factor-1(HIF-1) on tumour response to radiation the DWC/IVM model provided measurable differences in the microvascular density between HIF-1 deficient and HIF-1 competent tumours. The DWC/IVM model allowed the direct visualisation and quantification of the less well developed vasculature in HIF-1 deficient tumours compared to that found in HIF-1 competent tumours. The results provide a mechanistic basis for understanding the improved response to radiotherapy of HIF-1 deficient tumours.By applying the DWC/IVM model to conventional murine xenograft models the DWC/IVM proved itself as a useful research tool where continuous real-time non-invasive measurements could be made without the need for large numbers of time points or laborious histological analysis.
|Date of Award||1 Aug 2012|
- The University of Manchester
|Supervisor||Ian Stratford (Supervisor) & Kaye Williams (Supervisor)|
- Tumour vascular dorsal window radiation model