Identifying mechanisms of chronotolerance and chronoefficacy for the anticancer drugs 5-fluorouracil and oxaliplatin by computational modeling
Identifying mechanisms of chronotolerance and chronoefficacy for the anticancer drugs 5-fluorouracil and oxaliplatin by computational modeling
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DOI：
10.1016/j.ejps.2008.10.024
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发表时间：
2009-01-31
影响因子：
4.6
通讯作者：
Goldbeter, Albert
中科院分区：
文献类型：
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作者：
Altinok, Atilla;Levi, Francis;Goldbeter, Albert
我们使用细胞周期自动机模型来评估抗癌药物输送的各种昼夜节律模式的毒性，以提高癌症时间疗法的效率。基于细胞周期连续阶段 G1、S（DNA 复制）、G2 和 M（有丝分裂）之间的顺序转换，该模型允许我们模拟细胞周期阶段的分布以及生物钟的夹带。我们使用该模型来评估两种抗癌药物 S-氟尿嘧啶 (5-FU) 和奥沙利铂 (l-OHP) 的昼夜节律给药模式。我们首先考虑5-FU的情况，它对S期细胞发挥细胞毒作用。我们比较了最大给药时间不同的各种昼夜节律模式。该模型解释了为什么当峰值递送时间接近凌晨 4 点时获得最小的细胞毒性，这种给药时间模式在临床上用于 5-FU。我们还确定了在存在或不存在生物钟夹带的情况下，细胞周期阶段持续时间的变异性以及细胞周期长度如何影响细胞毒性。结果表明，相同的给药时间模式对一种细胞群（例如细胞）具有最小的细胞毒性。正常细胞，同时可以对第二细胞群（例如细胞）表现出高细胞毒性。肿瘤细胞。因此，该模型使我们能够发现可能有助于同时提高抗癌药物的时间耐受性和时间功效的因素。接下来我们考虑奥沙利铂的情况，与 5-FU 相比，奥沙利铂可以杀死细胞周期不同阶段的细胞。我们将血浆硫醇和细胞内谷胱甘肽的药代动力学纳入模型中，它们通过与药物形成无活性复合物来干扰药物的作用。该模型显示了血浆硫醇和谷胱甘肽水平的昼夜节律变化如何引起 l-OHP 细胞毒性的昼夜节律变化。模型的模拟证实了实验和临床结果，说明了最小化 l-OHP 细胞毒性的时间曲线与最小化 5-FU 细胞毒性的时间曲线是反相的。 (C) 2008 Elsevier B.V. 保留所有权利。
We use an automaton model for the cell cycle to assess the toxicity of various circadian patterns of anticancer drug delivery so as to enhance the efficiency of cancer chronotherapy. Based on the sequential transitions between the successive phases G1, S (DNA replication), G2, and M (mitosis) of the cell cycle, the model allows us to simulate the distribution of cell cycle phases as well as entrainment by the circadian clock. We use the model to evaluate circadian patterns of administration of two anticancer drugs, S-fluorouracil (5-FU) and oxaliplatin (l-OHP). We first consider the case of 5-FU, which exerts its cytotoxic effects on cells in S phase. We compare various circadian patterns of drug administration differing by the time of maximum drug delivery. The model explains why minimum cytotoxicity is obtained when the time of peak delivery is close to 4 a.m., which temporal pattern of drug administration is used clinically for 5-FU. We also determine how cytotoxicity is affected by the variability in duration of cell cycle phases and by cell cycle length in the presence or absence of entrainment by the circadian clock. The results indicate that the same temporal pattern of drug administration can have minimum cytotoxicity toward one cell population, e.g. of normal cells, and at the same time can display high cytotoxicity toward a second cell population, e.g. of tumour cells. Thus the model allows us to uncover factors that may contribute to improve simultaneously chronotolerance and chronoefficacy of anticancer drugs. We next consider the case of oxaliplatin, which, in contrast to 5-FU, kills cells in different phases of the cell cycle. We incorporate into the model the pharmacokinetics of plasma thiols and intracellular glutathione, which interfere with the action of the drug by forming with it inactive complexes. The model shows how circadian changes in l-OHP cytotoxicity may arise from circadian variations in the levels of plasma thiols and glutathione. Corroborating experimental and clinical results, the simulations of the model account for the observation that the temporal profiles minimizing l-OHP cytotoxicity are in antiphase with those minimizing cytotoxicity for 5-FU. (C) 2008 Elsevier B.V. All rights reserved.