期刊论文详细信息
JOURNAL OF THEORETICAL BIOLOGY 卷:253
Integrating cell-cycle progression, drug penetration and energy metabolism to identify improved cancer therapeutic strategies
Article
Venkatasubramanian, Raja1  Henson, Michael A.1  Forbes, Neil S.1 
[1] Univ Massachusetts, Dept Chem Engn, Amherst, MA 01003 USA
关键词: cell cycle;    drug penetration;    chemotherapy;    pharmacokinetics;    tumor growth model;   
DOI  :  10.1016/j.jtbi.2008.02.016
来源: Elsevier
PDF
【 摘 要 】

The effectiveness of chemotherapeutic drugs in tumors is reduced by multiple effects including drug diffusion and variable susceptibility of local cell populations. We hypothesized that quantifying the interactions between drugs and tumor microenvironments could be used to identify more effective anti-cancer strategies. To test this hypothesis we created a mathematical model that integrated intracellular metabolism, nutrient and drug diffusion, cell-cycle progression, cellular drug effects, and drug pharmacokinetics. To our knowledge, this is the first model that combines these elements and has coupled them to experimentally derived parameters. Drug cytotoxicity was assumed to be cell-cycle phase specific, and progression through the cell cycle was assumed to be dependent on ATP generation. The model consisted of a coupled set of nonlinear partial differential, ordinary differential and algebraic equations with an outer free boundary, which was solved using orthogonal collocation on a moving grid of finite elements. Model simulations showed the existence of an optimum drug diffusion coefficient: a low diffusivity prevents effective penetration before the drug is cleared from the blood and a high diffusivity limits drug retention. This result suggests that increasing the molecular weight of the anti-cancer drug paclitaxel from 854 to approximately 20,000 by nano-particle conjugation would improve its efficacy. The simulations also showed that fast growing tumors are less responsive to therapy than are slower tumors with more quiescent cells, demonstrating the competing effects of regrowth and cytotoxicity. The therapeutic implications of the simulation results are that (1) monolayer cultures are inadequate for accurately determining therapeutic effects in vitro, (2) decreasing the diffusivity of paclitaxel could increase its efficacy, and (3) measuring the proliferation fraction in tumors could enhance the prediction of therapeutic efficacy. (c) 2008 Elsevier Ltd. All rights reserved.

【 授权许可】

Free   

【 预 览 】
附件列表
Files Size Format View
10_1016_j_jtbi_2008_02_016.pdf 769KB PDF download
  文献评价指标  
  下载次数:0次 浏览次数:0次