| Apoptosis As cancer frequently results from an imbalance between cell proliferation and cell death, mutations in genes that result in a lack of appropriate cell death frequently contribute to the generation of cancer. Not surprisingly therefore, drugs targeting the apoptosis machinery to overcome the effect of these mutations are attractive candidates for the prevention and treatment of cancer. The mechanisms controlling cell death are inordinately complex but their understanding is critical for the development of effective cancer treatments. Physiomics has constructed a detailed mathematical model of apoptotic cell death that allows a systems analysis of the signalling pathways activated by various cell death-inducing stimuli, particularly those initiated by DNA damaging agents such as radiotherapy and chemotherapeutic agents (e.g. Cisplatin and the topoisomerase II inhibitors etopiside and mitoxantrone). Notably, the model can also simulate the effects of potentially novel classes of compounds. The model was created by the combined effort of the Physiomics team of biologists, mathematicians and computer scientists and is based on hundreds of research articles (Physiomics’ library contains over 3100 articles at last count). The Physiomics model includes over 120 reactions, over 80 species and more than 200 parameters and contains a mixture of stochastic equations and ordinary differential equations running in both single and multi-cellular simulations. An outline of the apoptosis model is shown in Figure 1.
The model has already been used to deliver significant value to our partners, supporting both positive and negative development decisions. The apoptosis model working in concert with our cell cycle model in a cell population environment (SystemCell® technology) provides a powerful means to simulate an array of different genetic changes that can cause cancer by altering the balance between proliferation and death (see our virtual tumour project). |
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