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.