Modeling the Transfer of Drug Resistance in Solid Tumors
Modeling the Transfer of Drug Resistance in Solid Tumors
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DOI：
10.1007/s11538-017-0334-x
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发表时间：
2017-10-01
影响因子：
3.5
通讯作者：
Levy, Doron
中科院分区：
文献类型：
--
作者：
Becker, Matthew;Levy, Doron
ABC外排转运蛋白是导致肿瘤多药耐药的关键因素。这些转运蛋白的过度表达显著降低了抗癌药物的疗效。在选择和诱导的同时，耐药也可能在细胞间转移，这是本文研究的重点。具体地说，我们考虑了P-糖蛋白(P-gp)的细胞间转移，这是一种众所周知的ABC转运蛋白，被证明对许多常见的化疗药物具有耐药性。在最近的一篇论文中，杜兰等人。(Bull Math Biol 78(6)：1218-1237,2016)研究了耐药和敏感的NCI-H460(人类非小肺癌)细胞株混合培养的动力学。不出所料，实验数据显示耐药细胞比例逐渐增加，敏感细胞比例下降。这项实验工作还伴随着一个数学模型，该模型假设P-gp从耐药细胞转移到敏感细胞，使它们暂时耐药。该数学模型对实验数据进行了合理的拟合。在这篇论文中，我们建立了一个新的癌细胞间耐药转移的数学模型。我们的模型是基于将耐药表型结合到癌症生长模型中(Greene等人。收录于J Theor Biol 367：262-277,2015)。由此产生的P-gp转移模型，被写成一个积分-微分方程组，遵循增殖、静止和凋亡细胞的动力学，具有不同的耐药表型。结果表明，该模型与Duran等人的实验数据具有很好的匹配性。(2016)。当耐药癌细胞的分裂速度慢于敏感细胞时，数学模型显示出更好的拟合度。
ABC efflux transporters are a key factor leading to multidrug resistance in cancer. Overexpression of these transporters significantly decreases the efficacy of anti-cancer drugs. Along with selection and induction, drug resistance may be transferred between cells, which is the focus of this paper. Specifically, we consider the intercellular transfer of P-glycoprotein (P-gp), a well-known ABC transporter that was shown to confer resistance to many common chemotherapeutic drugs. In a recent paper, Duran et al. (Bull Math Biol 78(6): 1218-1237, 2016) studied the dynamics of mixed cultures of resistant and sensitive NCI-H460 (human non-small lung cancer) cell lines. As expected, the experimental data showed a gradual increase in the percentage of resistance cells and a decrease in the percentage of sensitive cells. The experimental work was accompanied with a mathematical model that assumed P-gp transfer from resistant cells to sensitive cells, rendering them temporarily resistant. The mathematical model provided a reasonable fit to the experimental data. In this paper, we develop a new mathematical model for the transfer of drug resistance between cancer cells. Our model is based on incorporating a resistance phenotype into a model of cancer growth (Greene et al. in J Theor Biol 367: 262-277, 2015). The resulting model for P-gp transfer, written as a system of integro-differential equations, follows the dynamics of proliferating, quiescent, and apoptotic cells, with a varying resistance phenotype. We show that this model provides a good match to the dynamics of the experimental data of Duran et al. (2016). The mathematical model shows a better fit when resistant cancer cells have a slower division rate than the sensitive cells.