Understanding the effect of drugs on solid tumours presents a number of challenges owing to the complexity of the blood flow and drug transport, as well as the highly complex biochemical networks involved in the cellular response with characteristics of high non-linearity of signal transduction. It is imperative to develop a bottom-up systematic computational framework that is able to disentangle the multiple layers of complexity, to present mechanistic and predictive descriptions of drug effect on tumour cells and to allow the incorporation of other complexities. This study represents the first effort towards developing such a framework and includes the most essential modelling components: extracellular drug transport, intracellular signalling dynamics (target cellular apoptosis pathway) and the effect on the population density of cells. The integration of these components is also addressed in this study, where the strategy is to bypass the detailed and complex network of apoptosis by focusing on capturing its key qualitative features. The framework is further expanded by incorporating a drug-induced resistance module, which is modelled by applying negative feedback regulation to the target cellular apoptosis pathway. Two simplified but representative resistance modules are extracted from the literature and examined in the spatially distributed framework. Another feature of the model presented in this thesis is the integration of blood flow, which contributes to more detailed and heterogeneous drug distribution. As a bottom-up approach, the simplest geometry of tumour vasculature is adopted to capture the basic features of tumour blood flow and to allow further investigation into the interaction between drug transport and intracellular signalling within this context. It is demonstrated that a skeletal systems framework has been created which can serve as the basis of future systematic expansion to include additional aspects of cellular and tissue complexities.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:556529 |
| Date | January 2012 |
| Creators | Liu, Cong |
| Contributors | Xu, Xiao ; Krishnan, J. |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/9586 |
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