Lévi F, Filipski E, Iurisci I, Li X M, Innominato P
INSERM, U776 Rythmes biologiques et cancers, Hôpital Paul Brousse, Villejuif, F-94807, France.
Cold Spring Harb Symp Quant Biol. 2007;72:465-75. doi: 10.1101/sqb.2007.72.030.
The circadian clock orchestrates cellular functions over 24 hours, including cell divisions, a process that results from the cell cycle. The circadian clock and cell cycle interact at the level of genes, proteins, and biochemical signals. The disruption or the reinforcement of the host circadian timing system, respectively, accelerates or slows down cancer growth through modifications of host and tumor circadian clocks. Thus, cancer cells not only display mutations of cell cycle genes but also exhibit severe defects in clock gene expression levels or 24-hour patterns, which can in turn favor abnormal proliferation. Most of the experimental research actively ongoing in this field has been driven by the original demonstration that cancer patients with poor circadian rhythms had poor quality of life and poor survival outcome independently of known prognostic factors. Further basic research on the gender dependencies in circadian properties is now warranted, because a large clinical trial has revealed that gender can largely affect the survival outcome of cancer patients on chronotherapeutic delivery. Mathematical models further show that the therapeutic index of chemotherapeutic drugs can be optimized through distinct delivery profiles, depending on the initial host/tumor status and variability in circadian entrainment and/or cell cycle length. Clinical trials and systems-biology approaches in cancer chronotherapeutics raise novel issues to be addressed experimentally in the field of biological clocks. The challenge ahead is to therapeutically harness the circadian timing system to concurrently improve quality of life and down-regulate malignant growth.
昼夜节律时钟在24小时内协调细胞功能，包括细胞分裂，这是细胞周期产生的一个过程。昼夜节律时钟与细胞周期在基因、蛋白质和生化信号层面相互作用。宿主昼夜节律计时系统的破坏或强化，分别通过改变宿主和肿瘤的昼夜节律时钟来加速或减缓癌症生长。因此，癌细胞不仅表现出细胞周期基因的突变，而且在时钟基因表达水平或24小时模式上也存在严重缺陷，这反过来又有利于异常增殖。该领域目前正在积极开展的大多数实验研究，最初是由一项证明驱动的，即昼夜节律不良的癌症患者，其生活质量和生存结果较差，且与已知的预后因素无关。现在有必要对昼夜节律特性中的性别依赖性进行进一步的基础研究，因为一项大型临床试验表明，性别在很大程度上会影响癌症患者接受时辰治疗时的生存结果。数学模型进一步表明，根据初始宿主/肿瘤状态以及昼夜节律同步和/或细胞周期长度的变异性，通过不同的给药方案可以优化化疗药物的治疗指数。癌症时辰治疗中的临床试验和系统生物学方法提出了一些新问题，有待在生物钟领域通过实验加以解决。未来的挑战是在治疗上利用昼夜节律计时系统，以同时改善生活质量并下调恶性肿瘤生长。
