Clocks, cancer, and chronochemotherapy
Sancar A, Van Gelder RN. Clocks, cancer, and chronochemotherapy. Science 2021;371.
Correspondence to: ziz Sancar
The core of the mammalian circadian clock mechanism is a time-delayed transcription-translation feedback loop (TTFL), which influences the transcription and expression of a large fraction of the transcriptome. Through this mechanism, the mammalian circadian clock modulates many physiological functions, including the timing of cell division and rates of metabolism in specific tissues. Circadian clock dysfunction is associated with several human disease states, including jet lag and sleep phase disorders, and it likely contributes significantly to the development of metabolic syndrome. With respect to cancer, animal studies have suggested that specific carcinogenic mechanisms, such as ultraviolet radiation for skin cancer, have a strong circadian rhythm. Epidemiologic studies have yielded conflicting results as to whether circadian clock disruption by night or shift work is carcinogenic.In animal studies, tumors grafted into animals with disrupted rhythms grow more rapidly than those grafted into control animals. Studies of mice genetically lacking specific components of the circadian clock show increased rates of tumorigenesis for certain clock genes and certain tumors but show reduced rates for other clock genes. Similarly, the response to chemotherapy may also vary with time of day, which has led to enthusiasm for chronochemotherapy as a means to improve the therapeutic efficacy of cancer treatment while limiting toxicity. However, clinical trials of chronochemotherapy have generally not shown improved efficacy and have even shown worse outcomes in subsets of patients compared with conventionally timed therapies.
哺乳動物晝夜節律機制的核心是時間延遲的轉錄-翻譯反饋環（TTFL），它會影響大部分轉錄組的轉錄和表達。通過這種機制，哺乳動物生物鐘可以調節許多生理功能，包括特定組織中細胞分裂的時間和新陳代謝的速率。晝夜節律功能障礙與幾種人類疾病狀態相關，包括時差和睡眠階段障礙，它可能對代謝綜合症的發展做出重要貢獻。關於癌症，動物研究表明特定的致癌機制，例如皮膚癌的紫外線輻射，具有很強的晝夜節律。流行病學研究在晝夜節律性晝夜幹擾或輪班工作是否致癌方面產生了矛盾的結果。在動物研究中，移植到具有節律紊亂的動物中的腫瘤比移植到對照動物中的腫瘤生長更快。在基因上缺乏晝夜節律特定成分的小鼠的研究表明，某些生物鐘基因和某些腫瘤的發生率增加，而其他生物基因的發生率降低。類似地，對化學療法的響應也可能隨一天中的時間而變化，這引起了對時序化療的熱情，這是一種提高癌症治療的療效同時限制毒性的手段。然而，與常規定時療法相比，時序化療的臨床試驗通常並未顯示出改善的療效，甚至顯示出患者亞組的預後更差。
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