As reported by The Boston Globe, October 3, 2005.

You're Getting Sleepy; Could That Stop Cancer?

By Judy Foreman

Melatonin, long known to insomniac Americans as an over-the-counter sleep aid, is now being studied as a way to prevent and treat breast and other cancers.

Dubbed the ''hormone of darkness," melatonin is made by the brain's pineal gland at nighttime. This summer, researchers at Brigham and Women's Hospital led by Dr. Eva Schernhammer, an epidemiologist, showed that women who produced the lowest levels of melatonin were 70 percent more likely to get breast cancer than those with the highest levels.

Schernhammer's group previously showed that women who work at night are at higher risk of both breast and colon cancer. Light at night can shut off melatonin production.

A study to be published this fall explores whether women who sleep nine hours or more a night -- enabling them to produce more than the average amount of melatonin -- are at lower than average risk of breast cancer.

A coauthor of that study, cancer epidemiologist Richard Stevens of the University of Connecticut Health Center in Farmington, Conn., said breast cancer rates are much higher in industrialized countries, where, among other things, people routinely use a lot of artificial light at night, which suppresses melatonin production.

''We can't say yet, but the evidence is accumulating that light at night, and the consequent decrease in melatonin, may be a major driver of breast cancer," he said.

From an evolutionary point of view, melatonin may have developed as a signal to tell animals when to breed. In sheep, melatonin levels rise in the fall as the nights get longer, and ewes become fertile -- perhaps as nature's way of ensuring that when they give birth four months later, the weather will be balmier.

Melatonin is also an important regulator of the circadian clock in the brain, which keeps the body on a regular cycle of day and night. Light, whether from the sun or electric lights, suppresses melatonin production. But when light disappears, and darkness falls, there's a cascade of nerve signals from the eye to the pineal gland, which then starts making melatonin.

That's why melatonin has been popularized as a sleep aid. But a government study in 2004 found the melatonin pills on the market had limited effectiveness. A more recent study from the Massachusetts Institute of Technology suggests that the problem may simply be dosing: The pills that are currently sold in health food stores are many times too strong. A dose of only .3 milligrams helps people fall asleep faster, according to a study led by MIT's Richard Wurtman.

Frustrated by the high rates of breast cancer in industrialized countries, Stevens of UConn hypothesized in the late 1980s that light at night might spur cancer growth and that melatonin might protect against it.

''We know that if you take out the pineal gland in animals, that removes all melatonin, and then if you inject cancer cells, the cancer growth rate increases," said Steven Lockley, a neuroscientist at Brigham and Women's, who is now studying the melatonin levels and breast cancer rates of women who are blind. ''We know that when you put an animal in constant light, that also stops all melatonin production, and you get a similar response. And if you then treat an animal with melatonin, you can slow down the cancer rate."

Researchers are just now starting to look at the treatment potential for melatonin.

At the Bassett Research Institute in Cooperstown, N.Y., Dr. David Blask, a senior research scientist, reported at a cancer meeting this summer that melatonin can ''put cancer cells to sleep" by blocking their ability to soak up linoleic acid, which makes cancer cells grow rapidly. In animal studies, Blask said he has found that cancer cell growth is slower at night, when melatonin is highest, and faster during the day. He also found that adding melatonin to human breast cancer cells grown in rats can slow the cancer's growth.

In other animal studies, Steven Hill, vice chairman of structural and cellular biology at Tulane University in New Orleans, has found that melatonin binds to receptors on both normal and breast cancer cells. Once it lands on a receptor, he said, it affects chemical signals inside the cell to suppress estrogen, which drives many breast tumors. ''We can prevent 85 percent of mammary tumors in our rats with a combination of melatonin and retinoid [vitamin A]," he said.

In Europe, studies of people with cancer who are given melatonin are also promising, though preliminary. Melatonin appears able to not only slow cancer progression and improve survival in advanced cancer patients, but to protect healthy cells from the side effects of chemotherapy and radiation, said Dr. Fade Mahmoud, of the University of South Dakota School of Medicine, who published a review of the studies this summer.

Italian researchers, in a long series of human studies, have shown that melatonin, which appears to have little toxicity, can boost survival at least modestly in some people with melanoma and cancers of the lung, breast, kidney, and other organs.

These studies ''sound intriguing," said Dr. Mark Pegram, director of the Women's Cancer Program at the Jonsson Comprehensive Cancer Center at UCLA. ''But obviously more experimental studies are needed to evaluate whether or not melatonin may play a role in breast cancer growth regulation."

Spurred by the positive results, American researchers are starting to pay attention to melatonin. Dr. William Hrushesky, a senior clinician-investigator at the Dorn VA Medical Center in Columbia, S.C., and colleagues, are conducting a randomized, double-blind study with melatonin plus chemotherapy to see if melatonin helps lung cancer patients.

While it's too soon to rush out and buy over-the-counter melatonin to fight cancer, it is a good idea to ''live a melatonin-friendly lifestyle," said Stevens of UConn.

That means going to bed earlier if you're a night owl, making sure the bedroom is dark, and keeping the light dim in the bathroom if you make nightly trips there.

''The longer you stay in the dark," Stevens said, ''the more melatonin you're putting out."