Towards an integrated systems-based modelling framework for drug transport and its effect on tumour cells.
Towards an integrated systems-based modelling framework for drug transport and its effect on tumour cells.
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DOI：
10.1186/1754-1611-8-3
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发表时间：
2014
影响因子：
5.6
通讯作者：
Xu XY
中科院分区：
文献类型：
--
作者：
Liu C;Krishnan;Xu XY
系统地了解化疗对实体肿瘤的影响是非常具有挑战性和复杂性的，因为它包含了在多个尺度上发生的现象的相互作用。希望有一个多尺度的系统框架，能够解开多种促成因素的单独作用，例如运输和细胞外因素，以及纯粹的细胞内因素，以及这些因素之间的相互作用。基于最近开发的基于系统的建模框架，我们开发了一个耦合系统，通过在肿瘤中结合血管内和血管外药物运输，动态描述细胞内信号和肿瘤细胞密度动力学，进一步阐明药物运输的作用及其与细胞信号的相互作用。运输和细胞信号之间相互作用的不同方面以及运输参数的影响已经在Silico中进行了研究。有限的药物渗透性被发现是诱导药物效应的主要制约因素；运输与细胞信号相互作用的许多方面与细胞信号的细节无关。敏感性分析表明，药物扩散性的影响取决于间质药物转运和触发细胞凋亡的特定要求之间的平衡(由高度非线性的信号网络控制)，这表明在这种情况下药物扩散性的影响必须与细胞动力学的描述结合起来考虑。在这项研究中开发的模型框架为药物对肿瘤细胞的影响提供了定性和机械性的见解。它为研究细胞外因子(如转运)和细胞内因子之间的相互作用提供了一个电子实验平台。这样的平台对于理解运输和细胞因素在实体肿瘤中的单独和联合影响是必不可少的。
A systematic understanding of chemotherapeutic influence on solid tumours is highly challenging and complex as it encompasses the interplay of phenomena occurring at multiple scales. It is desirable to have a multiscale systems framework capable of disentangling the individual roles of multiple contributing factors, such as transport and extracellular factors, and purely intracellular factors, as well as the interactions among these factors. Based on a recently developed systems-based modelling framework, we have developed a coupled system in order to further elucidate the role of drug transport, and its interplay with cellular signalling by incorporating intra- and extra-vascular drug transport in tumour, dynamic descriptions of intracellular signalling and tumour cell density dynamics. Different aspects of the interaction between transport and cell signalling and the effects of transport parameters have been investigated in silico. Limited drug penetration is found to be a major constraint in inducing drug effect; many aspects of the interaction of transport with cell signalling are independent of the details of cell signalling. A sensitivity analysis indicates that the effect of drug diffusivity depends on the balance between interstitial drug transport and the specific requirement for triggering apoptosis (governed by highly nonlinear signalling networks), suggesting that the effect of drug diffusivity in such cases must be considered in conjunction with descriptions of cellular dynamics. The modelling framework developed in this study provides qualitative and mechanistic insights into the effect of drug on tumour cells. It provides an in silico experimental platform to investigate the interplay between extracellular factors (e.g. transport) and intracellular factors. Such a platform is essential to understanding the individual and combined effects of transport and cellular factors in solid tumour.
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影响因子：
--
作者：
Eikenberry, Steffen
通讯作者：
Eikenberry, Steffen
影响因子：
9.8
作者：
Albeck JG;Burke JM;Spencer SL;Lauffenburger DA;Sorger PK
通讯作者：
Sorger PK
影响因子：
4.8
作者：
El-Kareh, AW;Secomb, TW
通讯作者：
Secomb, TW
影响因子：
4
作者：
KOHN, KW;JACKMAN, J;OCONNOR, PM
通讯作者：
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影响因子：
3.4
作者：
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通讯作者：
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