title: Macrophage-based anti-cancer therapy: modelling different modes of tumour targeting.
abstract: Tumour hypoxia is associated with poor drug delivery and low rates of cell proliferation, factors that limit the efficacy of therapies that target proliferating cells. Since macrophages localise within hypoxic regions, a promising way to target hypoxic tumour cells involves engineering macrophages to express therapeutic genes under hypoxia. In this paper we develop mathematical models to compare the responses of avascular tumour spheroids to two modes of action: either the macrophages deliver an enzyme that activates an externally applied prodrug (bystander model), or they deliver cytotoxic factors directly (local model). The models we develop comprise partial differential equations for a multiphase mixture of tumour cells, macrophages and extracellular fluid, coupled to a moving boundary representing the spheroid surface. Chemical constituents, such as oxygen and drugs, diffuse within the multiphase mixture. Simulations of both models show the spheroid evolving to an equilibrium or to a travelling wave (multiple stable solutions are also possible). We uncover the parameter dependence of the wave speed and steady-state tumour size, and bifurcations between these solution forms. For some parameter sets, adding extra macrophages has a counterintuitive deleterious effect, triggering a bifurcation from bounded to unbounded tumour growth. While these features are common to the bystander and local models, the crucial difference is where cell death occurs. The bystander model is comparable to traditional chemotherapy, with poor targeting of hypoxic tumour cells; however, the local mode of action is more selective for hypoxic regions. We conclude that effective targeting of hypoxic tumour cells may require the use of drugs with limited mobility or whose action does not depend on cell proliferation.
authors.affiliation: Centre for Mathematical Medicine, School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Webb
authors.forename: Markus R
authors.initials: MR
authors.lastname: Owen
authors.forename: Helen M
authors.initials: HM
authors.lastname: Byrne
authors.forename: Craig
authors.initials: C
authors.lastname: Murdoch
authors.forename: Claire E
authors.initials: CE
authors.lastname: Lewis
mesh_terms: D000465:Algorithms; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015687:Cell Hypoxia / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003198:Computer Simulation; D003520:Cyclophosphamide / Q000378:metabolism / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use; D014162:Transfection
chemical_list: D004798:Enzymes; D011355:Prodrugs; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System