A growing body of evidence from both animal and human studies indicates that circadian rhythms - the biological rhythms that mimic the 24-hour cycle of the turning of the Earth - influence cancer in a variety of ways.

In mice and rats, disruption of circadian rhythms has been shown to increase the rate at which a variety of cancers develop. Epidemiologic studies have found elevated rates of breast cancer in women and prostate cancer in men whose circadian rhythms are disrupted as a result of working rotating day and night shifts.

The efficacy and toxicity of more than 30 anticancer drugs has been shown in animal studies to vary by more than 50 percent depending on the time of day that treatment is delivered. Clinical trials, conducted primarily in patients with colon cancer, have found as much as a twofold improvement in antitumor activity and a fivefold improvement in patient tolerability when infusions of chemotherapeutic agents are timed to circadian rhythms.

At least 12 genes are known to be involved in the regulation of circadian rhythms. Loss or dysregulation of circadian genes has been identified in many types of cancer. Moreover, overexpression of certain circadian genes in cancer cells has been shown to inhibit the cells' growth and increase their rate of apoptosis (programmed cell death).

Until recently, scientists thought circadian rhythms were entirely controlled by a "master clock" in the brain known as the suprachiasmatic nucleus (SCN). Recent research has shown that, in fact, virtually all cells - including tumor cells - possess their own circadian "clocks," a discovery that has opened up new avenues for research.

One intriguing finding is that whereas the SCN is synchronized primarily by the daily light-dark cycle, cellular circadian rhythms are strongly influenced by meal timing. Mice inoculated with osteosarcomas lived longer when fed during the day rather than at night (when they would normally eat, because mice are nocturnal).

Now, with funding from NCI, two research teams whose work has contributed to current understanding of the role of circadian rhythms in cancer are trying to further this line of research by probing the possible links among circadian rhythms, timing of food intake, caloric restriction, nutritional therapy, and cancer prevention.

Nutritional substances
Dr. Jack D. Burton and his colleagues at the Garden State Cancer Center in Belleville, NJ, previously found in a mouse model of breast cancer that the drug celecoxib showed circadian variation in both efficacy and toxicity. At specific times of day, the dose of the drug could be escalated 2.5-fold with no increase in side effects.

Another of Dr. Burton's research interests is the use of nutritional substances to treat and prevent cancer. Because many studies have shown circadian effects for anticancer drugs, he wondered whether nutritional agents might show similar effects.

"Many nutritional substances have been found to have both antitumor and chemopreventive effects in various animal models," he says. "But they hadn't previously been tested in a way that focused on the time of administration."

In pilot studies, the researchers administered selenium and curcumin (an ingredient in the spice turmeric) at various times to mice with implanted, human-derived prostate tumors. They found differences in the degree of inhibition of tumor growth depending on the time of administration and identified potential tumor markers that might explain this effect.

On the basis of this pilot work, Dr. Burton's group obtained NCI funding for a larger study to assess in a rat model of prostate cancer whether the chemopreventive effects of selenium and green tea extract are modulated by circadian-based administration. In this model, the rats develop prostate cancer gradually, mimicking the disease process in humans.

Caloric restriction
Dr. Alec J. Davidson of Morehouse School of Medicine in Atlanta has previously shown that in transgenic rats with chemically induced liver cancer, restricted daytime feeding alters the circadian rhythms in the liver, with the pattern of disruption differing in cancer cells compared with healthy tissue.

"We showed that the clock in liver cancer cells differs from that in adjacent healthy cells in the same animal," he explains. "So is there a causal connection? And is the clock altered because the cells are cancerous or did something go wrong with the clock first?"

Previous work by others had suggested that a calorically restricted diet could prevent cancer and lengthen life. "We wondered whether the apparent effect of caloric restriction was really the result of a circadian change. Maybe feeding at the 'wrong' time - that is, during the day for animals that are naturally nocturnal - creates an unnatural state that affects tumors more negatively than the rest of the animal."

With NCI funding, Dr. Davidson and his colleagues are now testing this hypothesis in a mouse model of prostate cancer. "We are using restricted daytime feeding as one of many potential ways to alter the cellular clock, to see whether manipulating circadian timing accelerates or inhibits cancer growth," he says.

"This research is important because the results suggest that, although an emphasis on new drug development is appropriate and certainly necessary, the effect of timing of new and old drugs might be equally important areas of research for potential therapeutic advances," noted Dr. Jeff White, director of NCI's Office of Cancer Complementary and Alternative Medicine.

—Eleanor Mayfield