Chronotherapy

Tuesday, May 9th, 2017

Keeping the body’s cells synced up matters for health:

In 2007, based on epidemiological studies, the International Agency for Research on Cancer declared shift work, which causes circadian disruption, a carcinogen. Other studies have elucidated a link between immune cell activity and glucocorticoids—which are secreted in circadian patterns and regulate peripheral clocks—as well as a role for chronic stress in perturbing daily cycles in gene expression, which can alter immune, endocrine, and other functions.

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Genes involved in cell division were among the earliest identified as being rhythmically expressed in both rodent models and human cells. In 1987, researchers studying ovarian cancers found that tumor cells synthesized DNA on a daily rhythm that typically peaked in the late morning hours, nearly 12 hours out of sync with nontumor cells. This led the team to suggest that timing chemotherapy doses that target cells actively replicating their DNA might improve the drugs’ effectiveness while reducing healthy-cell death.

Sure enough, over the past 30 years, experimental models and clinical trials have found that timing chemo regimens can significantly affect their toxicity and effectiveness. In animal studies of nearly 30 chemo drugs, tailoring dosing time to the medication’s mode of action has been found to decrease toxic side effects and increase effectiveness. In one study, rats that received the chemotherapy drug cisplatin at the time of day when their urinary output was highest (a correlate of other timed cycles in kidney metabolism) had fewer nephrotoxic effects, as measured in kidney function tests, than animals that received the doses at the time of minimum urinary output. In another study, oxaliplatin chemotherapy caused fewer intestinal lesions and less bone marrow suppression in mice when given at night, possibly because DNA synthesis in murine bone marrow is highest during the day.

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Clinical trials in 1985 found that antihistamines were most effective when taken at night or early in the morning. Subsequent studies established that inhaling corticosteroids at bedtime, or using delayed-release prednisone formulations that allocated the medication to the body pre-dawn, were most effective at combating allergy symptoms. Cardiovascular events were also recognized early on to cycle throughout the day, as doctors noticed that most patients admitted for heart attacks tended to experience their symptoms between 6:00 a.m. and noon.

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