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肿瘤多细胞球体和单层培养物中药物转运的数学建模。

Mathematical modelling of drug transport in tumour multicell spheroids and monolayer cultures.

作者信息

Ward John P, King John R

机构信息

Division of Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, NG7 2RD, Nottingham, UK.

出版信息

Math Biosci. 2003 Feb;181(2):177-207. doi: 10.1016/s0025-5564(02)00148-7.

Abstract

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.

摘要

在本文中,我们采用一种无血管肿瘤生长模型来比较药物作用于多细胞球体和单层培养物的效果。肿瘤模型基于活细胞连续体的营养驱动生长,其生死导致的体积变化由速度场描述。药物被建模为一种外部施加的、可扩散的能够杀死细胞的物质,正在研究药物作用于细胞的线性和米氏动力学。将多细胞球体情况下所得偏微分方程组的数值解与单层情况下的封闭形式解进行比较,特别是关于药物剂量及其作用持续时间对细胞杀伤的影响。结果表明,与单层培养物相比,多细胞球体中的存活率有所提高,这与实验观察结果一致,并表明决定这一现象的关键因素是药物渗透。对固定浓度下持续施加药物的长时间肿瘤球体反应进行分析,发现多达三种稳定的长时间解,即平凡解(即死亡肿瘤)、行波解(持续生长的肿瘤)和亚线性生长情况,其中核心细胞达到伪稳态。对每种可能性进行了阐述和研究,并讨论了它们之间的分岔情况。数值解表明,伪稳态解比行波解能承受显著更高的药物剂量。

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