title: A systems-based mathematical modelling framework for investigating the effect of drugs on solid tumours.
abstract: BACKGROUND
  Elucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly non-linear chemical signal transduction. Appropriate systems frameworks are needed to seriously address the sources of these complexities, especially from the cellular side.
  
  
  RESULTS
  We develop a skeletal modelling framework incorporating interstitial drug transport, intracellular signal processing and cell population descriptions. The descriptions aim to appropriately capture the nature of information flow. The model is deliberately formulated to start with simple intracellular descriptions so that additional features can be incorporated in a modular fashion. Two kinds of intracellular signalling modules which describe the drug effect were considered, one a monostable switch and the other a bistable switch. Analysis of our model revealed how different drug stimuli can lead to cell killing in the tumour. Interestingly both modules considered exhibited similar trends. The effects of important parameters were also studied.
  
  
  CONCLUSIONS
  We have created a predictive systems platform integrating drug transport and cellular response which can be systematically augmented to include additional layers of cellular complexity. Our results indicate that intracellular signalling models which are qualitatively different can give rise to similar behaviour to simple (and typical) stimuli, and that validating intracellular descriptions must be performed with care by considering a variety of drug stimuli.
authors.affiliation: Chemical Engineering and Chemical Technology, Imperial College London, South Kensington, London SW7 2AZ, UK.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Krishnan
authors.forename: Xiao Yun
authors.initials: XY
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007267:Injections; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology / Q000379:methods*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents