Cancer Clock

Summer is here and outdoor enthusiasts are enjoying the longer days offered by June, July and August. But soon we’ll find ourselves back in the darkness of winter, surrounded by artificial light. This, scientists are learning, can wreck havoc on the internal time-keeping mechanism that keeps track of the 24-hour day. Without this circadian cycle, animals would never know when to sleep, wake up or eat. But the body’s clock may also be involved in more advanced processes, such as tumor growth. While some studies have shown a link between circadian disruption and cancer susceptibility, others suggest that synchronizing medications with a patient’s circadian rhythms may lead to cancer therapies.

It was 20 years ago that Richard Stevens, now a cancer epidemiologist at University of Connecticut Health Center, proposed that prolonged exposure to light at night disrupts circadian rhythms, interrupting the production of melatonin, the hormone that regulates sleep-wake cycles. Stevens also suggested that normal levels of melatonin could slow the growth of cancer cells, particularly in breast cancer.

In 2006, researchers found data verifying this link. A study published in the January 2006 issue of Epidemiology concluded that women who work on rotating night shifts for an extended period of time (thus disrupting their inherent biological clocks) are about 79 percent more likely to develop breast cancer than other women.

“If you disrupt your circadian rhythms by light exposure, you disrupt the production of melatonin. It takes about five to seven days for a person to entrain into a new rhythm,” says Eva Schernhammer, researcher at Brigham and Women’s Hospital and lead author of the Epidemiology study. It is during this adaptation period that melatonin levels are not quite as high, she explains. This is a particular problem for shift workers, like nurses.

Nurses are an ideal group to study circadian clock disruption because they tend to have schedules that rotate between days and nights. Two long-term cohort studies funded by the National Institutes of Health, the Nurses Health Study I and II, are probing the effects of shift work on women and their risk of breast cancer. Researchers collect blood, urine and DNA samples from female nurses and analyze them for, among other things, melatonin levels. They then examine melatonin levels in women who developed breast cancer. “Higher levels of melatonin provide better protection from breast cancer,” says Schernhammer.

As researchers develop a better understanding of biological time, they’re using their knowledge to improve drug therapies. In a practice known as chronotherapy, medicine is delivered in different doses at various times of the day, taking into account the body’s natural rhythms and cycles.

“The idea [of chronotherapy] came quite a while ago from certain observations that people made in clinical practice. Doctors observed that the therapeutic effect of medicine could be quite different at different times of the day,” says Marina Antoch, a researcher at the Lerner Research Institute in Cleveland, Ohio, who studies the influence of the circadian clock on cancer therapy.

Cancer therapy is an ideal field for researching chronotherapeutic approaches. Humans’ sensitivity to drug treatments varies greatly, depending on the time of application. Taking into account biological rhythms when administering cancer therapies not only reduces the toxic effects of the drugs, but also allows patients to receive higher medication doses more effectively.

While chronotherapy can be applied to other treatments, Antoch notes that cancer therapy provides a unique situation to study the practice. “You want to kill as many cancer cells as possible, but if you increase the dose, you can kill healthy cells,” she explains. Because the circadian clock is responsible for controlling normal tissues and cancer tissues, says Antoch, it makes a good model for finding a treatment more specifically targeted towards cancer cells and less damaging to normal cells.

There are two ways to use chronotherapy. In one model, if doctors know that a drug will have fewer side effects and produce a better response at a certain time of day, they administer it then. This approach requires the doctor to know, or figure out, the most beneficial time for treatment. And if the best time happens to be in the middle of the night, treatment is inconvenient for the both the medical personnel and the patient.

But there is another way to think about chronotherapy. In humans, the circadian cycle is controlled by tens of thousands of cells in a region of the brain called the suprachiasmatic nucleus. Rather than catering to the body’s biological time, researchers are working to develop ways to reset the brain’s circadian clock so that it responds better to drug therapies given at specific times.

This is the approach Antioch’s lab is working on. “It’s a lot more attractive to use a pharmacological approach, and it makes chronotherapy more standardized,” she says. “We have a long way to go, but it’s a very promising approach,” says Antoch.