Mechanistic mathematical modelling of mercaptopurine effects on cell cycle of human acute lymphoblastic leukaemia cells.
Mechanistic mathematical modelling of mercaptopurine effects on cell cycle of human acute lymphoblastic leukaemia cells.
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DOI：
10.1038/sj.bjc.6602893
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发表时间：
2006-01-16
影响因子：
8.8
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中科院分区：
文献类型：
--
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抗代谢药巯基嘌呤（MP）被广泛用于治疗儿童急性淋巴细胞白血病（ALL）。为了研究MP对细胞周期的动力学，我们将人T细胞白血病细胞系（Molt-4敏感和耐药亚系以及P12耐药）与10 μM MP孵育，并在72 h内连续测量总细胞计数、细胞周期分布、存活百分比、凋亡百分比和死亡百分比。我们开发了用MP处理后细胞周期动力学的数学模型，并使用它来显示Molt-4敏感对照相对于抗性细胞系具有显著更高的细胞进入凋亡的速率（2.7倍，P<0.00001）。此外，当用MP处理时，敏感细胞系显示与其对照相比细胞进入凋亡的速率显著增加（2.4倍，P<0.00001）。值得注意的是，耐药细胞系具有更高的抗代谢物掺入活细胞DNA的速率（>1.4倍，P<0.01）。最后，与其他细胞系相反，Molt-4抗性亚系继续循环，尽管相对于其对照的速率较慢，而不是进行细胞凋亡。这导致Molt-4抗性细胞系中更大的S期阻滞，但没有更高的细胞死亡率。细胞凋亡，细胞周期和修复基因的基因表达与模型描述的机制动力学是一致的。总之，该数学模型提供了定量评估，以比较MP在具有不同程度MP抗性的细胞中的细胞周期效应。
The antimetabolite mercaptopurine (MP) is widely used to treat childhood acute lymphoblastic leukaemia (ALL). To study the dynamics of MP on the cell cycle, we incubated human T-cell leukaemia cell lines (Molt-4 sensitive and resistant subline and P12 resistant) with 10 μM MP and measured total cell count, cell cycle distribution, percent viable, percent apoptotic, and percent dead cells serially over 72 h. We developed a mathematical model of the cell cycle dynamics after treatment with MP and used it to show that the Molt-4 sensitive controls had a significantly higher rate of cells entering apoptosis (2.7-fold, P<0.00001) relative to the resistant cell lines. Additionally, when treated with MP, the sensitive cell line showed a significant increase in the rate at which cells enter apoptosis compared to its controls (2.4-fold, P<0.00001). Of note, the resistant cell lines had a higher rate of antimetabolite incorporation into the DNA of viable cells (>1.4-fold, P<0.01). Lastly, in contrast to the other cell lines, the Molt-4 resistant subline continued to cycle, though at a rate slower relative to its control, rather than proceed to apoptosis. This led to a larger S-phase block in the Molt-4 resistant cell line, but not a higher rate of cell death. Gene expression of apoptosis, cell cycle, and repair genes were consistent with mechanistic dynamics described by the model. In summary, the mathematical model provides a quantitative assessment to compare the cell cycle effects of MP in cells with varying degrees of MP resistance.
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影响因子：
3.6
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