The circadian timing system in clinical oncology
The circadian timing system in clinical oncology
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DOI：
10.3109/07853890.2014.916990
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发表时间：
2014-06-01
影响因子：
4.4
通讯作者：
Levi, Francis A.
中科院分区：
文献类型：
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作者：
Innominato, Pasquale F.;Roche, Veronique P.;Levi, Francis A.
昼夜节律计时系统 (CTS) 在 24 小时内控制癌症过程和治疗效果的多个关键分子途径，包括药物代谢、细胞周期、细胞凋亡和 DNA 损伤修复机制。这导致抗癌剂的全身和细胞药代动力学和药效学具有昼夜节律时间依赖性。然而，基于对休息活动、体温、睡眠和/或激素分泌节律的昼夜节律监测，癌症患者的 CTS 稳健性和阶段有所不同。在高达 50% 的转移性癌症患者中进一步发现昼夜节律紊乱。这种干扰与不良结果相关，包括疲劳、厌食、睡眠障碍以及较短的无进展生存期和总生存期。新颖的微创设备使非住院癌症患者能够进行持续的 CTS 评估。他们揭示了个体昼夜节律阶段长达 12 小时的差异。总而言之，这些数据支持时间疗法的个性化。这种治疗方法旨在根据昼夜节律调整癌症治疗的实施，使用可编程的时间泵或新型释放制剂，以提高疗效和耐受性。根据一项荟萃分析，与传统分娩相比，固定奥沙利铂、5-氟尿嘧啶和亚叶酸时间治疗方案可将转移性结直肠癌男性的中位总生存期延长 3.3 个月 (P = 0.009)。进一步的分析表明，接受时间疗法的患者需要预防昼夜节律紊乱或恢复强大的昼夜节律功能，以进一步优化治疗效果。加强外部同步器可以通过有计划的锻炼、进餐时间、光照、改善社会支持、睡眠安排以及针对生物钟的适当定时药物给药来实现这一目标。时间康复需要临床测试来改善癌症患者的生活质量和生存率。
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.