UNC study supports role of circadian clock in response to chemotherapy

CHAPEL HILL, 14 jan 2009 – For years, research has hinted that the time of day that cancer patients receive chemotherapy can impact their chances of survival. But the lack of a clear scientific explanation for this finding has kept clinicians from considering timing as a factor in treatment.

Now, a new study from the University of North Carolina at Chapel Hill has suggested that treatment is most effective at certain times of day because that is when a particular enzyme system – one that can reverse the actions of chemotherapeutic drugs – is at its lowest levels in the body.

The study, performed in mice, could also have implications for the prevention of new cancers.

The enzyme system implicated – called nucleotide excision repair– repairs many types of DNA damage that come not just from chemotherapy but also from the ultraviolet rays of the sun. Thus, by understanding the cyclical nature of this system, physicians may be able to pinpoint when it is most crucial for people to protect themselves from sun exposure to minimize their risk of skin cancer.

"Timing is everything, and here we have molecular data showing why this is especially true with regard to cancer," said senior study author Aziz Sancar, M.D., Ph.D., a member of the UNC Lineberger Comprehensive Cancer Center and Sarah Graham Kenan professor of biochemistry and biophysics in the UNC School of Medicine. Sancar is also a member of the National Academy of Sciences and the Turkish Academy of Sciences. "By hitting cancer cells with chemo at a time when their ability to repair themselves is minimal, you should be able to maximize effectiveness and minimize side effects of treatment."

The study, set to appear this week in the online early edition of the Proceedings of the National Academy of Sciences, provides the first solid evidence that the daily oscillations of the cell's repair machinery can affect the potency of cancer drugs.

The primary driver of this oscillatory behavior is the circadian clock, which keeps the biochemical, behavioral and physiological processes of many organisms, including mice and humans, on a 24-hour cycle. Every single cell in the body – whether from the kidney, liver or heart – has its own internal clock, and each of these are synchronized and coordinated by one master clock, located in a particular cluster of neurons in the brain.

Because of the important role that the circadian clock plays in regulating the daily rhythms of life, Sancar wanted to see what influence it had on important functions in the body, in particular the repair of damage to DNA caused by chemotherapy or UV radiation. This damage is usually repaired by a process called nucleotide excision repair, which cuts out and replaces sections of damaged DNA.

Sancar and his colleagues studied the behavior of the repair machinery in cerebrum or brain tissue of mice over the course of a day, and found that the ability to repair damage was at a minimum in the early morning and reached a maximum in the evening hours. They then looked at each of the six components that make up the repair machinery and found that the levels of one of them – the enzyme XPA – rose and fell in synchrony with the oscillations of the circadian clock. Thus, the researchers demonstrated that the cell's ability to repair damage is linked to the circadian clock, and that this daily oscillation is ultimately due to changes in the levels of one particular enzyme at different times of day.

Sancar now wants to extend these studies to determine whether the same cyclical changes in repair activity seen in mouse brain can also be observed in mouse testis. This avenue is particularly relevant because cisplatin – a chemotherapeutic agent commonly used to treat testicular cancer – kills cancer cells by damaging DNA.

While cisplatin is considered by many people to be a miracle drug – it completely cured Lance Armstrong – one in ten patients who take it still do not survive and it is not as effective on other cancers, such as colon, ovarian and lung cancers. Sancar said he believes that identifying the times when the cancer cells' ability to repair damage is at a minimum may enable clinicians to tailor treatment and improve the survival rate for people with testicular cancer and these other more common cancers as well.

He also would like to see his findings being used for cancer prevention. Because the enzyme Sancar identified also repairs damage caused by sunlight, he plans to determine if the repair capacity in human skin changes as a function of the time of day.

"If we show the same patterns in humans as we did in mice, then it could tell us when would be the safest time to be in the sun (2 p.m. to 6 p.m.), and when would be the best time to avoid sun exposure (6 a.m. to 10 a.m.)," Sancar said. "The new information could help us prevent skin cancers."

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The research was supported by the National Institutes of Health. Study co-authors from UNC department of biochemistry and biophysics include the lead author and postdoctoral scientist Tae-Hong Kang, Ph.D.; senior research associate Joyce T. Reardon; and postdoctoral scientist, Michael Kemp, Ph.D.

Guidelines Issued for Management of Circadian Rhythm Sleep Disorders
November 5, 2007 — The American Academy of Sleep Medicine (AASM) has issued practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders (CRSDs), which are published in the November 1 issue of Sleep.
"The expanding science of circadian rhythm biology and a growing literature in human clinical research on circadian rhythm sleep disorders (CRSDs) prompted the American Academy of Sleep Medicine (AASM) to convene a task force of experts to write a review of this important topic," write Timothy I. Morgenthaler, MD, and colleagues from the Standards of Practice Committee of the AASM. "These practice parameters were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the AASM to present recommendations for the assessment and treatment of CRSDs based on the two accompanying comprehensive reviews. The main diagnostic tools considered include sleep logs, actigraphy, the Morningness-Eveningness Questionnaire (MEQ), biologic phase markers, and polysomnography."
The accompanying review includes 2 sections: the first including a general introduction to circadian biology, as well as "exogenous" CRSDs (shift work disorder and jet lag disorder), and the second highlighting the "endogenous" CRSDs (advanced sleep phase disorder, delayed sleep phase disorder, irregular sleep-wake rhythm, and the non–24-hour sleep-wake syndrome [nonentrained type] or free-running disorder).
Both reviews summarize the peer-reviewed scientific literature published through October 2006, and the authors evaluated the evidence according to the Oxford System for Evidence-Based Medicine. Using this evidence, the Standards of Practice Committee and Board of Directors of the AASM determined levels of treatment recommendation, ranging from standard (highest level of certainty) through guideline (intermediate level) to option (weakest level).
Other recently published updated practice parameters addressed the use of actigraphy and light therapy, so key findings from these were summarized in the present AASM statement.
Specific recommendations are as follows:
Use of a sleep log or diary is indicated to evaluate patients with suspected CRSD (guideline).
Actigraphy is indicated to facilitate the assessment of patients with suspected CRSDs. Depending on which CRSD is suspected, the strength of recommendation varies from "Option" to "Guideline."
Polysomnography is not routinely indicated for the diagnosis of CRSDs. However, polysomnography may be needed to exclude another primary sleep disorder (standard).
For routine clinical evaluation of CRSDs, evidence is insufficient to justify the use of MEQ (option).
Although biologic phase markers are useful to determine circadian phase and confirm the diagnosis of free-running disorder in sighted and unsighted patients, evidence is insufficient to recommend their routine use in the diagnosis of shift work disorder, jet lag disorder, advanced sleep phase disorder, delayed sleep phase disorder, or irregular sleep-wake rhythm (option).
Actigraphy is a useful outcome measure in determining the response to treatment of CRSDs (guideline). Available treatments include planned sleep schedules, timed light exposure, timed melatonin doses, hypnotics, stimulants, and alerting agents.
Planned or prescribed sleep schedules are indicated in jet lag disorder, shift work disorder, delayed sleep phase disorder, advanced sleep phase disorder, irregular sleep-wake rhythm, (except for elderly, nursing home residents with dementia) and free-running disorder (option).
Specifically dosed and timed light exposure is indicated for each of the circadian disorders, although success varies based on the specific diagnosis (option).
Timed melatonin administration is indicated for shift work disorder, advanced sleep phase disorder, and free-running disorder in sighted individuals (option); for jet lag disorder, delayed sleep phase disorder, and free-running disorder in unsighted persons (guideline); and for irregular sleep-wake rhythm in children who have moderate to severe psychomotor retardation (option).
To promote or improve daytime sleep among night shift workers, hypnotic medications may be indicated (guideline).
Hypnotic medications may also be indicated to treat jet lag–induced insomnia (option).
Although stimulants may be indicated to improve alertness in jet lag disorder and shift work disorder (option), they may have associated risks that should be carefully considered before use.
For patients with shift work disorder, modafinil may be indicated to improve alertness during the night shift (guideline).
"We acknowledge that while the disorders are classified as endogenous or exogenous, the physiologic underpinnings of each disorder are not so surgically separated," the authors conclude. "In reality, combinations of endogenous and exogenous factors lead to the manifestations of each disorder."
All members of the AASM Standards of Practice Committee and Board of Directors were found to have disclosed no relevant financial relationships pertinent to this topic.
Sleep. 2007;00:000-000.