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.
