title: The Role of Oxygen in Avascular Tumor Growth.
abstract: The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model.
authors.affiliation: Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.
authors.forename: David Robert
authors.initials: DR
authors.lastname: Grimes
authors.affiliation: Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Pavitra
authors.initials: P
authors.lastname: Kannan
authors.affiliation: The Weatherall Institute for Molecular Medicine, University of Oxford, John Radcliffe Hospital/Headley Way, Oxford, OX3 9DS, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: McIntyre
authors.affiliation: Advanced Technology Development Group, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kavanagh
authors.affiliation: Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Abul
authors.initials: A
authors.lastname: Siddiky
authors.affiliation: The Weatherall Institute for Molecular Medicine, University of Oxford, John Radcliffe Hospital/Headley Way, Oxford, OX3 9DS, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Wigfield
authors.affiliation: The Weatherall Institute for Molecular Medicine, University of Oxford, John Radcliffe Hospital/Headley Way, Oxford, OX3 9DS, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Harris
authors.affiliation: Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Partridge
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D010100:Oxygen; D000093542:Gemcitabine