what time is it? Your body knows this is based on a carefully calibrated internal clock that turns certain genes on and off throughout the day. Humans have long known that certain medicines are best used at different times of the day: caffeine Morning, for example.
what to do if it’s cancer druggiven to individual patients at specially adjusted times, could work better and have fewer side effects?
That’s the hope of scientists working on “timed chemotherapy.” But researchers say both scientific and practical issues mean the method isn’t ready for prime time.
“We’re still in the learning curve,” says Jane Campian, MD, a neuro-oncologist at the Mayo Clinic in Rochester, Minnesota.
The challenge for cancer drugs is to maximize the killing of cancer cells while keeping healthy cells alive. The body’s natural internal clock can help limit toxicity, says oncologist and researcher Francis Levy, MD, of the University of Paris-Saclay. The trick is to find a time when healthy cells are spared from the drug, or able to break them down into something that won’t harm them — which cancer cells can’t do. Tumor cells often have dysfunctional internal clocks, so they may be more vulnerable to treatment if healthy cells are protected, Lévi said.
one cancer treatment What seems to be a difference in timing is that the combination of 6-mercaptopurine and methotrexate is used for some types of leukemia in children. For example, a 1985 study found that 36 children who took their medication in the morning were 4.6 times more likely to relapse than 82 children who took their medication in the evening. Based on this and other research, doctors usually recommend taking both drugs in the evening.
But for most cancer drugs, there is little or no evidence for the effect of time of day.
Campian and colleagues recently asked whether time had an effect on drugs Temozolomide in people with brain cancer Glioblastoma. They already had data on who took the drug in the morning or at night. That’s because Campian is trained to tell patients to take it at night so they can fall asleep with unpleasant side effects like nausea, but other doctors who work with her recommend taking it in the morning.
When the researchers reviewed their 166 patients, they found that those who took temozolomide in the morning lived longer. This suggests a difference in timing, but retrospective studies like this are hard to prove an effect.
Next, the team started a new study asking patients if they could schedule their medication at a specific time and whether the drug would work better in the morning. In the small study, among 35 adults with brain tumors, participants recorded in diaries the times they took their medication, which showed they were more than 90 percent correct at the time of day. The results differed from previous studies, in which people who took the drug in the morning did not survive longer than those who took it in the evening.
Whether timing temozolomide would have an effect is an open question because of conflicting results from two small studies.The next step is to go back to the lab to better understand how the effects of temozolomide change over time daily routine, said co-author Dr. Erik Herzog, a biologist at Washington University in St. Louis. Larger studies are needed to test whether this type of chronotherapy actually works in people, and how much of a difference it makes.
Lévi has tested timed chemotherapy in hundreds of colorectal cancer patients. In his trial, half of the 564 people received standard treatment, which included three drugs. Others received the same drugs, but their IVs were timed so two drugs would peak in the early morning and one drug would peak in the afternoon.
The results were mixed. On the positive side, men’s risk of death dropped by 25% with timed treatment.But in women, timed chemotherapy Increase The risk of premature death was reduced by 38%.
The difference, Lévi said, may be because males and females have different circadian rhythm-controlling genes, leading to a five- to six-hour difference in response to the drug.
not so fast
Lévi’s results illustrate a key challenge with timed chemotherapy: How do you know when everyone should get their drug? Does the dosing regimen have to be individualized for each patient?
Sex isn’t the only problem. Some people are morning larks. Others are night owls. The researchers envision using activity monitors on patients’ wrists to figure out their unique schedule before prescribing timed chemotherapy.
At the same time, some cancers disrupt the body’s internal clock, which may render timed chemotherapy methods moot.
There are also practical challenges in delivering strictly timed drugs.
You can take oral medications like temozolomide any time you are awake. But what about drugs that need to be injected intravenously? Inpatients have the potential to receive strictly timed treatment at any time, said Dr. Belinda Mandrell, director of nursing research at St. Jude Children’s Research Hospital in Memphis. Lévi prefers programmable medication pumps that can meter medication at home.
The bigger challenge, however, is figuring out whether timed chemotherapy works. Aziz Sancar, MD, a biochemist at the University of North Carolina at Chapel Hill, is skeptical.He says more work should be done in cells and mice Clinical Trials It is suitable for people.
“I’m not saying it will never work,” he said. “I don’t think chronotherapy is here yet, and I don’t know if it will.”