INSERM, UMRS 776 'Biological Rhythms and Cancers', Campus CNRS , 7 rue Guy Môquet, 94801 Villejuif Cedex , France.
Ann Med. 2014 Jun;46(4):191-207. doi: 10.3109/07853890.2014.916990.
The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest- activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P=0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving quality of life and survival in cancer patients.
生物钟计时系统 (CTS) 控制着癌症过程和治疗效果在 24 小时内的几个关键分子途径，包括药物代谢、细胞周期、细胞凋亡和 DNA 损伤修复机制。这导致了抗癌药物在全身和细胞水平上的药代动力学和药效学的昼夜节律依赖性。然而，根据对静息-活动、体温、睡眠和/或激素分泌节律的昼夜节律监测，CTS 的稳健性和相位在癌症患者之间存在差异。在多达 50%的转移性癌症患者中进一步发现了生物钟紊乱。这种紊乱与不良结局有关，包括疲劳、厌食、睡眠障碍以及无进展生存期和总生存期缩短。新型微创设备使非住院癌症患者能够连续进行 CTS 评估。他们发现个体生物钟相位存在长达 12 小时的差异。综合这些数据，支持个体化时间治疗。这种治疗方法旨在根据生物钟节律调整癌症治疗的给药，使用可编程时间泵或新型释放制剂，以提高疗效和耐受性。一项奥沙利铂、5-氟尿嘧啶和亚叶酸钙时间治疗方案的荟萃分析显示，与常规给药相比，转移性结直肠癌男性患者的中位总生存期延长了 3.3 个月（P=0.009）。进一步的分析表明，需要在接受时间治疗的患者中预防生物钟紊乱或恢复稳健的生物钟功能，以进一步优化治疗效果。通过有计划的运动、用餐时间、光照、改善社会支持、睡眠安排以及恰当地给予靶向生物钟的药物，可以增强外部同步器来实现这一目标。时间康复需要进行临床测试，以提高癌症患者的生活质量和生存率。
