Mathematical modelling of drug transport in tumour multicell spheroids and monolayer cultures.
In this paper we adapt an avascular tumour growth model to compare the effects of drug application on multicell spheroids and on monolayer cultures. The model for the tumour is based on nutrient driven growth of a continuum of live cells, whose birth and death generates volume changes described by a velocity field. The drug is modelled as an externally applied, diffusible material capable of killing cells, both linear and Michaelis-Menten kinetics for drug action on cells being studied. Numerical solutions of the resulting system of partial differential equations for the multicell spheroid case are compared with closed form solutions of the monolayer case, particularly with respect to the effects on the cell kill of the drug dosage and of the duration of its application. The results show an enhanced survival rate in multicell spheroids compared to monolayer cultures, consistent with experimental observations, and indicate that the key factor determining this is drug penetration. An analysis of the large time tumour spheroid response to a continuously applied drug at fixed concentration reveals up to three stable large time solutions, namely the trivial solution (i.e. a dead tumour), a travelling wave (continuously growing tumour) and a sublinear growth case in which cells reach a pseudo-steady-state in the core. Each of these possibilities is formulated and studied, with the bifurcations between them being discussed. Numerical solutions reveal that the pseudo-steady-state solutions persist to a significantly higher drug dose than travelling wave solutions.
Ward
John P
JP
Division of Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, NG7 2RD, Nottingham, UK. john.ward@lboro.ac.uk
King
John R
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics; D006801:Humans; D016685:Mitomycin / Q000493:pharmacokinetics; D008954:Models, Biological; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009716:Numerical Analysis, Computer-Assisted; D018874:Spheroids, Cellular / Q000378:metabolism
D000970:Antineoplastic Agents; D016685:Mitomycin; D004317:Doxorubicin