As reported by the Washingtonian, January 17, 2007.

Cancer and the Rhythms of Your Body

By John Pekkanen

Do the body’s day and night rhythms hold an answer to cancer? Researchers who think so don’t like a lot of light at night.

One night in 1985, Richard Stevens awoke and noticed a streetlight beaming into his apartment window. “The light was almost bright enough for me to read by,” he says, “and I thought: What about that? What about light at night?”

An epidemiologist, Stevens had been puzzling over the marked increase in breast cancer over the past several decades. Evidence of that increase came from many sources, including the Connecticut Tumor Registry, which has the country’s longest history of tumor data. Those statistics revealed that the incidence of breast cancer for women 40 and older had been on the rise for almost 50 years.

The bright streetlight prompted Stevens, then with the Department of Energy’s Pacific Northwest National Lab, to think of cancer in a new way. In a 1987 American Journal of Epidemiology, Stevens published a paper, “Electric Power Use and Breast Cancer: A Hypothesis,” in which he argued that exposure to light at night might explain part of the upsurge in breast cancer.

The paper was radical for its time. But in recent years, Stevens’s ideas have gained currency and become a topic of interest for the National Institutes of Health.

His theory rests on the fact that artificial light at night disrupts the body’s circadian rhythm, the internal 24-hour clock common to mammals and other biological organisms. In humans, these rhythms are orchestrated by the suprachiasmatic nucleus, or SCN, the body’s master clock that sits above the brain stem, near the optic nerves. Acutely sensitive to light, the SCN transmits signals to the body’s cells and coordinates their activity throughout the 24-hour day.

Each organ and cell in humans has a core of nine “clock” genes. Taking cues from the SCN, these genes control daily oscillations of enzymes and hormones that affect the timing of cell function, division, and growth. Body temperature, immune responses, digestion, visual and mental sharpness, and pain tolerance all undergo cyclic changes that peak and ebb at fixed times each day. Afternoon, for example, is the best time to see a dentist.

In his 1987 study, Stevens focused on how light disrupts the production of melatonin, a chemical secreted at night by the brain’s pineal gland and best known for helping to regulate sleep-wake cycles. Melatonin supplements are sold over the counter as a sleep aid and to ward off jet lag.

The brain may secrete up to 20 times more melatonin at night than in the daytime, peaking between 2 and 3 am. Thus it is nicknamed “the hormone of darkness.”

Stevens cited animal research going back to the 1960s suggesting that melatonin possessed anticancer properties. To test his theory, Stevens wanted to see if women who worked night shifts would be at higher risk for cancer. He contacted Harvard’s Dr. Walter Willet, director of the ongoing Nurses Health Study, the largest and longest-running collection of health and lifestyle data on American women. Willet included questions about shift work in a 1988 questionnaire sent to 75,000 nurses.

The resulting data showed that nurses who did shift work for 30 years or more had a 36-percent higher incidence of breast cancer than nurses who worked days. After that study, others found similar links between nighttime circadian disruption and breast cancer. Animal research also uncovered a connection between melatonin suppression and breast cancer. Studies of blind women revealed they have a lower incidence of breast cancer than sighted women.

For all American women, the lifetime risk of breast cancer has risen from one in 11 in 1975 to one in eight today, according to the National Cancer Institute. New imaging techniques that came into wide use in the early 1980s can account for some, but not all, of the increase.

“The body of evidence supports the theory that circadian disruption, and probably the involvement of melatonin, is part of the reason for the high incidence of breast cancer in industrialized nations,” Stevens says, “where women are at much higher risk of breast cancer than women in nonindustrialized countries, even after accounting for age.”

He says breast cancer is increasing at a rapid rate in newly industrialized areas of the world and suspects light at night may be part of the reason why.

Exposure to light at night also may increase the incidence of other cancers. The Nurses Health Study revealed shift workers to be at increased risk of colon cancer. This fall, a study of 14,052 Japanese male workers concluded that shift workers who alternated between day and night work were three times more likely to develop prostate cancer than day workers. Men who worked exclusively at night were also at higher risk, but not as much as the shift workers. The study, published in the American Journal of Epidemiology, accounted for age and other risk factors such as family history, smoking, alcohol consumption, and weight.

Stevens suspects circadian disruption may also be implicated in depression, obesity, diabetes, and other disorders. “Disrupting these rhythms cannot be healthy for us,” he says. “We do it at our peril.”

Although it’s possible to reset your circadian clock by sleeping during the day, Stevens says as a practical matter this doesn’t happen. Darkness is the key for melatonin secretion, and people seldom sleep by day in the required degree of darkness for eight or nine hours.

“There are clearly major differences among people on the amount of night light that will affect melatonin secretion,” says Stevens, who’s now at the University of Connecticut Health Center. “Some people are much more sensitive to the light-suppressive effects of melatonin than others.”

Stevens recently completed a study with Finnish colleagues that found that women who slept nine hours at night had a lower breast-cancer risk than women who slept less than eight hours. For some people, getting up at night and turning on bright lights even for a few minutes disrupts the circadian clock.

According to Stevens, researchers are trying to develop lighting for night workers that’s less disruptive of circadian rhythms.

Stevens’s research raises an intriguing prospect. If light at night increases cancer risk by suppressing melatonin, could boosting the body’s supply of melatonin help treat or prevent cancer?

Three years ago, Dr. David Blask, a neuroendocrinologist at the Bassett Research Institute in upstate New York, devised an experiment to help answer this question. Blask, who’s been studying melatonin and cancer for nearly 30 years, obtained blood from female medical students at three different times—during the day, at night under dark conditions, and late at night after the women were awakened and exposed to bright light for 90 minutes.

Blood drawn in the daytime and after the women were exposed to light at night had very low melatonin levels, while blood drawn in the dark was rich in melatonin.

Blask then pumped the three sets of blood into human breast tumors implanted in rats. Some of the tumors were characteristic of aggressive tumors seen in younger, premenopausal women. Others were more typical of those found in postmenopausal women, which comprise the majority of breast cancers.

Tumors given the blood with low melatonin levels exhibited very rapid cell proliferation and an increased metabolism. They also took in high amounts of linoleic acid, a fatty acid that feeds and fuels tumors.

But when Blask fed the melatonin-rich blood to the tumors, their growth and metabolic activity slowed dramatically, up to 70 to 80 percent. To confirm that melatonin caused this slackening, Blask added a chemical that blocked its action. Sure enough, the tumors reacted the same as those given the low-melatonin blood.

“Nothing is ever absolute in science, but that’s as close as you can get to proving that melatonin is what brought tumor activity to a near halt,” says Blask, who published his findings in a 2005 issue of Cancer Research.

“When there is light at night to markedly diminish melatonin secretion,” he says, “the cancer cells become insomniacs, if you will, and are active 24/7 instead of waxing and waning.”

Blask’s study is the strongest evidence yet to support the light-cancer connection that Stevens first suggested. Blask, whose research has been supported by the National Cancer Institute, says his experimental models indicate the metabolism of cancer increases anywhere from two to five times as fast under low-melatonin conditions.

Melatonin appears to have several anti­tumor effects. It not only quiets tumor activity; it also seeks out and destroys free radicals, reactive byproducts of normal cell division that have been linked to aging and many disorders, including cancer.

But Blask, Stevens, and other researchers believe melatonin’s strongest anticancer value is that it helps prevent linoleic acid from entering the cancer cells.

We need some linoleic acid in our diet, but many of us consume too much because it is plentiful in many foods, including corn chips and other corn products, snack foods, and some cooking oils such as corn, sunflower, and safflower oil.

Dr. Jeffrey White, director of the office of complementary and alternative medicine at the National Cancer Institute, organized a conference in 2003 on melatonin and cancer. “Melatonin was a topic that had been touched upon in different parts of the cancer research community, much of it outside the US, and I wanted to stimulate discussion about it and bring people up to date,” White says.

Among those at the conference was Italian researcher Dr. Paolo Lissoni, who has spent more than 20 years investigating melatonin and the treatment of cancer. Lissoni reported on a randomized study in which melatonin doses of 20 to 40 milligrams (very high doses in comparison to what is naturally secreted) were given every 24 hours at night to 1,440 patients with untreatable, advanced solid tumors.

In his summary, Lissoni reported that the melatonin had several benefits. It prolonged survival time and prevented physical deterioration, though most of the tumors did not regress.

Lissoni summarized another study of 450 cancer patients in a weakened state or with chemotherapy-resistant tumors. Melatonin, according to Lissoni, prolonged survival time, prevented certain side effects of chemotherapy, and seemed to slow tumor progression.

Lissoni further reported that melatonin, when given with tamoxifen, a breast-cancer medication, seemed to inhibit tumor growth in 14 metastatic-breast-cancer patients whose cancers were progressing on tamoxifen alone. In a small percentage of patients with untreatable, advanced solid tumors, he found that melatonin alone caused some tumors to regress.

Other studies from Spain, South Africa, Germany, and France have suggested that melatonin may be of use in the treatment of some cancers. Laboratory studies have found that melatonin inhibits the growth of prostate-cancer cells. In one small study, melatonin in conjunction with conventional medical treatment improved survival rates in patients with metastatic prostate cancer.

Not every study has shown a melatonin benefit. Dr. Lawrence Berk, an associate professor of radiation oncology at the H. Lee Moffitt Cancer Center & Research Institute at Tampa General Hospital, recently completed an NCI-funded melatonin trial on 126 brain-cancer patients whose life expectancy was estimated to be about four months. The trial was similar to Lissoni’s: Some patients received chemotherapy; others got radiation therapy along with melatonin.

Berk says the trial found no increased survival time for the melatonin group. Blask, who took part in Berk’s study, thinks that the patients were in the study for too short a time. “I don’t think melatonin had enough chance to work,” he says.

Berk and Blask agree on one point: The study did not prove that melatonin does not work. “All we can say is in this particular trial, it didn’t,” Berk says. “But a single trial cannot answer the question as to whether melatonin works or not.”

He adds: “There’s a big difference between preventing cancer and treating cancer. Once you have cancer, it’s a different ball game.”

Key questions about melatonin and cancer remain. Although melatonin supplements have not produced side effects in studies, the long-term consequences of altering circadian rhythms are not known. Another uncertainty is the dosage. Lissoni used 20 milligrams for his research, yet Blask’s study found a strong antitumor effect at very low levels, or roughly the normal level in the body.

“As of now,” Blask adds, “melatonin dosage for cancer treatment or prevention is guesswork.”

Blask and Berk say they would like to see research into whether melatonin might help prevent some cancers. White of the NCI notes that data suggest melatonin might have cancer-prevention properties but warns that “there are many more pieces of the puzzle that have to be found.”

Finding those pieces won’t be easy. “Long-term prospective human prevention trials are huge and expensive,” White says. He cited an unfinished study on the impact of vitamin-E supplements on prostate cancer that has cost upward of $100 million.

Drug companies helped fund the early trial of tamoxifen, but they aren’t likely to offer major support for studies of melatonin. The chemical is widely available commercially and is not a proprietary substance, so the pharmaceutical industry doesn’t stand to profit from it.

The National Cancer Institute, the most likely funder, has seen its purse strings tightened by Congress in recent years, says White: “Since before 2003, we’ve had substantially less increase in our budget, and we’re at the lowest level of grant funding in a long time. We’re funding less than 20 percent of all our major grants right now.”

Like many researchers, Blask says he is uncertain whether his federal research grant will be renewed.

Carolina Hinestrosa of the Washington-based National Breast Cancer Coalition is open to the idea that melatonin could benefit cancer treatment and prevention. But she says more data are needed.

“Ultimately with any intervention and treatment for cancer we need to see the hard endpoints—survival and mortality for breast cancer,” Hinestrosa says. “The melatonin story has not been completely answered at this point. We need to go all the way by doing the right clinical studies.”

Even without further studies, Blask and other researchers have demonstrated that cancer cells don’t run at full throttle around the clock. Like the rest of the body, they seem to follow circadian rhythms and have their own sleep/wake cycles.

What that means for cancer treatment is the focus of research for Dr. William Hrushesky. For more than 30 years, Hrushesky has investigated the effect of circadian rhythms on cancer treatment—specifically, how the time of day that chemotherapy is administered can affect its chances for success.

An adjunct professor at the University of South Carolina, Hrushesky conducted his early research at the University of Minnesota and the National Institutes of Health. He contends that the time of day a specific chemotherapeutic drug is given has a major impact on its effectiveness and toxic side effects. In a study of 43 women with ovarian cancer who received eight months of chemotherapy, he found that the patients who received cisplatin in the evening tolerated the drug far better those who received it in the morning. The women in the morning group suffered kidney damage and a profound anemia, among other side effects. Given in the morning, Hrushesky says, the cisplatin poisoned a protein hormone produced by the kidney that stimulates red-blood-cell production.

Hrushesky saw the opposite result among patients given 5-FU, a chemotherapy agent that preferentially attacks cells that are rapidly dividing. Patients tolerated the drug far better when receiving it in the morning rather than the evening, when some of the body’s cells typically divide rapidly.

“If you are given an antiproliferative agent like 5-FU at a time of day when the cells lining the gut and bone marrow are proliferating like crazy,” Hrushesky says, “you’re going to blast the hell out of them. But if you give the drug at another time of day when they’re asleep, they’re going to be protected.”

Knowing when various normal cells are active is key, Hrushesky says: “It’s the difference between having permanent damage to organ systems or not.” Hrushesky’s other research suggests that timing chemotherapy based on circadian rhythms results in fewer infections, less bleeding, and less nausea.

Hrushesky also cites “increasing evidence” that giving anticancer drugs in the appropriate circadian phase significantly enhances their effectiveness. In his study of the women with ovarian cancer, four times as many patients survived five years if they received the anti­cancer drug doxorubicin in the morning and cisplatin in the evening.

“The safest and least toxic schedule was also the most effective,” Hrushesky says.

His most recent paper, published last year in Molecular Cancer Therapeutics, reported that when 5-FU was administered in the early morning, it resulted in less toxicity and generated the “greatest antitumor effect, and best survival.”

Hrushesky’s findings remain controversial. White of the National Cancer Institute says circadian-based cancer treatment is more widely accepted in Europe, but the data are “not consistent” in terms of whether it reduces tumor mass.

In September, the National Institutes of Health sponsored a two-day conference called “Environmental Influences on Circadian Rhythms and Human Disorders.” NIH is taking the issue seriously and thinks the cancer-research community should begin doing the same.

“Although we have developed new drugs to control toxic effects, we really ask patients to suffer a lot of toxicity,” White says.

Twenty years after Richard Stevens noticed a streetlight beaming into his bedroom, the hard evidence on the role that our bodily rhythms play in illnesses and treatment is not yet in. But the data suggest that he was on to something.

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