What is the time? Based on an internal clock that regulates gene activity throughout the day, your body can tell. People have known for years that certain medicines work best at different times of the day. caffeineMorning, to name one.
What if there is cancer? MedicinesIndividually tailored times could help to reduce side effects and make the drug more effective.
That’s the hope of scientists working on “chronochemotherapy.” But researchers say that both scientific and practical issues mean the approach isn’t ready for prime time.
“We’re still kind of in the learning curve,” says Jian Campian, MD, a neuro-oncologist at the Mayo Clinic in Rochester, MN.
Time Trials
The problem with cancer drugs is that they must maximize the killing of cancer cells and leave healthy ones behind. The body’s natural internal clock could help limit toxicity, says Francis Lévi, MD, an oncologist and researcher at Paris-Saclay University. The trick would be to find a time when healthy cells are protected against the drugs or are able to break them down into something that doesn’t harm them – but while cancer cells can’t do that. Tumor cells often have dysfunctional internal clocks, so they’re likely to be more susceptible to treatment at times when healthy cells are protected, says Lévi.
One Treatment for cancerCombining 6-mercaptopurine with methotrexate to treat certain types of cancer is an example of timing that seems to matter. leukemia in children. In 1985, a study found that children who took the drugs in morning were 4.6 times as likely to relapse as those who took them in the evening. These and other studies support the recommendation that doctors recommend this combination of drugs in the evening.
However, most cancer medications have little or no evidence that time of day has an effect on the effectiveness of their drugs.
Campian and his colleagues asked recently if the timing of the drug’s release made any difference. temozolomidePeople with brain cancer glioblastoma. They already had data about people who took it in the morning and evening. That’s because Campian was trained to tell patients to take it in the evening, so they could sleep through unpleasant side effects like nausea, but other doctors she worked with suggested taking it in the morning.
Researchers looked at 166 patients to see that people who had taken temozolomide the morning before survived better. Although this suggests that the timing of the dose can make a difference in survival, a look-back study such as this is unlikely to prove an effect.
The team began a new study asking if patients could take their medication at a certain time and if the drug would perform better in the morning. The study included 35 participants with brain tumours. They kept track of the times they took their medication in a diary. This showed that they were more likely to take the drug at the right time than the rest of the day. This study was different than the one before it. People who took the drug in their mornings didn’t last as long as people who took it in their evenings.
With conflicting results from two small studies, it’s an open question as to whether timing temozolomide makes a difference. The next step will be to return to the laboratory and study how temozolomide efficiency might differ with different patients. circadian rhythmsErik Herzog PhD, a collaborator at Washington University in St. Louis, states that this is the case. To test whether chronotherapy is effective in treating people with chronic pain, it would take a much larger study.
Lévi has already tested chronochemotherapy in hundreds of people with colorectal cancer. Half of the 564 participants in the trial were treated with the standard treatment. This included three medications. All the others were given the same drugs but their IVs were timed so that two of the meds would peak in the morning, and one in the afternoon.
Mixed results were observed. On the positive side, men’s risk of death dropped by 25% on the timed treatment. However, chronochemotherapy is more popular among women. IncreasedThe risk of death earlier than expected is 38%
Lévi says the difference may be because circadian rhythms control genes differently in men and women, leading to a 5- to 6-hour difference in response to medications.
Not so fast
Lévi’s results illustrate a key challenge in chronochemotherapy: How do you know when each person should get their meds? Do patients have to be given the same dosing schedule?
Sex isn’t the only issue. Some people are morning larks. Some are night owls. Researchers envision using activity monitors on patients’ wrists to figure out their unique schedules before prescribing chronochemotherapy.
Meanwhile, some cancers disrupt the body’s internal clock, which could make a chronochemotherapy approach moot.
It is not easy to provide precise medicine when you are trying to time it.
You could take oral medications like temozolomide any time you’re awake. But what about IV-based drugs? It could be possible for hospital inpatients to receive tightly timed therapies at any hour, says Belinda Mandrell, PhD, director of nursing research at St. Jude Children’s Research Hospital in Memphis. Lévi prefers programmable drug pumps that can meter out meds at home.
The larger challenge is to find out if chronochemotherapy really works. Aziz Sancar MD and PhD, a biochemist at University of North Carolina Chapel Hill has doubts. He suggests that there should be more research in cells and mice. Clinical trialsIn people are appropriate.
“I don’t say it’ll never work,” he says. “I think chronotherapy is not there yet, and I don’t know if it’ll ever be there.”
