INSERM, U Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France.
Annu Rev Pharmacol Toxicol. 2010;50:377-421. doi: 10.1146/annurev.pharmtox.48.113006.094626.
The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.
昼夜节律计时系统由分子钟组成，驱动 24 小时内的外源物代谢和解毒、细胞周期事件、DNA 修复、细胞凋亡和血管生成的变化。细胞昼夜节律时钟通过内源性生理节律进行协调，因此在可能被抗癌药物损伤的宿主组织中同步计时。因此，昼夜节律计时可以在实验模型和癌症患者中改变 2 到 10 倍的抗癌药物耐受性。由于 (a) 肿瘤固有昼夜节律的适应性差和 (b) 健康组织持续的昼夜节律适应性，当药物在各自最佳耐受性时间附近给药时，也会看到疗效的提高。相反，每当抗癌药物在毒性最大的时间给药时，宿主时钟就会被打乱。另一方面，昼夜节律紊乱会加速实验和临床癌症进程。性别、昼夜生理、时钟基因和细胞周期对癌症时间治疗的结果有重要影响。数学和系统生物学方法目前正在开发和整合理论、实验和技术工具，以进一步优化和个性化癌症治疗的昼夜节律给药。
