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When it comes to treating cancer, timing is everything — early detection, precise dosing schedules. But time of day? Aziz Sancar thinks that the susceptibility of tumors to anticancer therapy depends in part on the biological clock, the body’s daily timekeeping mechanism.

In an oscillating pattern called circadian rhythm, cells throughout the body adjust their functions over a twenty-four-hour period in sync with the cycle of the sun. The rhythm is controlled by a light-sensitive master clock in the brain and coordinates vital physiological processes such as body temperature, blood pressure, and the sleep-wake cycle.

Clinical observations have suggested that time of day affects cancer patients’ responses to chemotherapy. But doctors haven’t understood the physiology of this phenomenon, so chemotherapy regimens don’t include time-of-day criteria.

Sancar hypothesized that the underlying link between circadian rhythm and chemotherapy effectiveness is the DNA damage response — the natural process by which cells restore damaged DNA. Sancar points out that many anticancer drugs work by lethally damaging the DNA of tumor cells. “So we then considered DNA repair as a factor, because whether the damage is repaired will determine whether the cancer cell dies,” he says.

Sancar’s team found that DNA repair activity in a mouse brain is ten times higher in the late afternoon than in the early morning. He has experiments under way to measure circadian regulation of DNA repair in other mouse and human tissues. His goal is to identify the time of day when chemotherapy-induced DNA damage has the greatest advantage over the body’s natural DNA repair activity.

Scientists know that general interference with the biological clock can affect vulnerability to cancer. Epidemiological studies have shown that female populations including night-shift nurses and other nighttime workers have a higher incidence of breast cancer than those who work traditional hours.

“Disrupting the clock predisposes animals to cancer — this was the dogma,” Sancar explains. But the dogma lacked a biological explanation.

Sancar’s genetic approach to answering this question yielded surprising results: eliminating one of the four key components of the biological clock machinery, a protein called cryptochrome, actually delayed cancer formation in mice susceptible to tumors.

The lab found that cancer cells that lack cryptochrome die more readily than other cancer cells by a process known as apoptosis. It is this increase in apoptosis that essentially protects the animal from tumor growth.

Sancar is confident his findings will spur exciting work on the circadian regulation of cancer. “These findings tell us there is this connection. To translate this to clinical medicine will be a big challenge, and we will have to fine-tune it,” he says.

Kate Pedone was a student who formerly contributed to Endeavors.

Kate Pedone is a postdoc in the Lineberger Comprehensive Cancer Center. Aziz Sancar is the Sarah Graham Kenan Professor of Biochemistry and Biophysics in the School of Medicine and a member of the Lineberger Comprehensive Cancer Center. His findings were published in two papers in the February 24, 2009 issue of the Proceedings of the National Academy of Sciences.