A Strategy to Delay the Development of Cisplatin Resistance by Maintaining a Certain Amount of Cisplatin-Sensitive Cells.
A Strategy to Delay the Development of Cisplatin Resistance by Maintaining a Certain Amount of Cisplatin-Sensitive Cells.
复制标题
通过维持一定数量的顺铂敏感细胞来延缓顺铂耐药性发展的策略
DOI：
10.1038/s41598-017-00422-2
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发表时间：
2017-03-27
影响因子：
4.6
通讯作者：
Zou X
中科院分区：
文献类型：
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作者：
Duan G;Tang Q;Yan H;Xie L;Wang Y;Zheng XE;Zhuge Y;Shen S;Zhang B;Zhang X;Wang J;Wang W;Zou X
顺铂（ddp）通常用于治疗许多晚期癌症，通常会取得初步治疗成功；然而，耐药细胞的快速进展仍然是治疗失败的主要原因。针对这一问题，我们研究了耐药细胞系和耐药细胞系的适应度差异。我们发现，由于ROS水平升高，ddp耐药细胞的生长明显慢于敏感细胞，这表明ddp耐药机制可能对耐药细胞的生长产生负面影响。此外，我们观察到，当与ddp敏感细胞混合时，ddp抗性细胞无法竞争，因此在体内处理可以抑制ddp抗性细胞的生长。我们提出了一个基于体内实验参数化的数学模型来描述由两个竞争亚克隆组成的肿瘤的异速生长。根据我们的模型，提出了一种不同给药间隔的定量策略来控制肿瘤的生长。我们的策略利用肿瘤内竞争，适当的给药间隔可以显著延缓ddp耐药的发展，延长总生存期。维持一定数量的ddp敏感细胞，而不是通过持续治疗来根除肿瘤，对于未来的肿瘤治疗是可行的。
Cisplatin (ddp), which is commonly employed in the treatment of many advanced cancers, often results in initial therapeutic success; however, rapid progression of ddp-resistant cells remains the main reason for treatment failure. Facd with such a problem, we investigated the fitness differences between ddp-sensitive and ddp-resistant cell lines. We found that the growth of ddp-resistant cells was significantly slower than that of sensitive cells due to elevated ROS levels, which suggested that the ddp resistance mechanisms may have negative impacts on the growth of resistant cells. Furthermore, we observed that, when mixed with ddp-sensitive cells, ddp-resistant cells failed to compete, and the growth of ddp-resistant cells could therefore be suppressed by treatmentin vivo. We propose a mathematical model parameterized based onin vivoexperiments to describe the allometric growth of tumors consisting of two competing subclones. According to our model, a quantitative strategy with a variant drug-dosing interval is proposed to control tumor growth. Taking advantage of intratumoral competition, our strategy with appropriate dosing intervals could remarkably delay the development of ddp resistance and prolong overall survival. Maintaining a certain number of ddp-sensitive cells rather than eradicating the tumor with continuous treatment is feasible for future tumor treatment.