January 26, 2009

Time of Day Can Be Critical in Chemotherapy

A photo of a clock

The time of day that chemotherapy drugs are taken may be a major factor in the effectiveness of the treatment and the extent of its side effects, according to a new study. The results have important implications for cancer treatment.

Our body's daily rhythms are synchronized with the sun and coordinated by the body's circadian clock. While a region of the brain operates as the master biological clock, the system is complex and operates in virtually every cell of the body. It regulates our sleep, body temperature, eating habits and activity level. When our circadian rhythms are disrupted, sleep disorders may arise, as well as a host of other problems, including obesity, depression, heart disease, high blood pressure and diabetes.

The effectiveness and side effects of chemotherapy drugs are already known to be affected by the time of delivery. Cisplatin and other popular cancer treatments work in part by damaging the DNA of cancer cells. The cells fight the drugs by fixing the damage. A research team headed by Dr. Aziz Sancar at the University of North Carolina School of Medicine thought that it might be possible to take advantage of the body’s circadian rhythms to hit cancer cells when they’re least able to recover.

To investigate, the researchers made brain tissue extracts from mice at different times of day. Then they tested how well the extracts repaired damaged DNA by an important mechanism called excision repair. Their work was funded by NIH’s National Institute of General Medical Sciences (NIGMS).

The researchers reported in the online edition of the Proceedings of the National Academy of Sciences on January 21, 2009, that extracts taken from mouse brains in the morning repaired damaged DNA samples 6-7 times faster than those taken at night. To pinpoint the proteins involved, they analyzed the levels of 6 core excision repair proteins over a 24-hour period. Levels of one DNA damage repair protein called xeroderma pigmentosa A (XPA) proved to be much higher in the mouse brains during the day than at night.

To confirm that reduced excision repair at night was affected by low levels of XPA, the scientists added known amounts of XPA to the extracts. Adding extra XPA to the samples taken at night increased their ability to repair damaged DNA samples. In contrast, for samples collected in the morning, the extra XPA had little effect on the ability to repair damaged DNA. These results support the idea that DNA repair depends at least in part on fluctuating levels of XPA.

“Timing is everything, and here we have molecular data showing why this is especially true with regard to cancer,” Dr. Sancar said. “By hitting cancer cells with chemotherapy at a time when their ability to repair themselves is minimal, you should be able to maximize effectiveness and minimize side effects of treatment.”

However, the researchers note that the effect of daily time on DNA repair may be different in normal cells than in cancer cells. Further studies of both normal cells and cancer cells in humans will be needed before researchers can take advantage of circadian rhythms to design more effective cancer treatment regimens.

—by Dario Dieguez, Jr., Ph.D. and Harrison Wein, Ph.D.

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