Timing of chemo affects inflammation, mice study suggests
Finding ‘sweet spot’ for drug administration could help patients
COLUMBUS – The time of day that breast cancer chemotherapy drugs are given affects the amount of damaging inflammation in the body, a new study in mice suggests.
That’s important because inflammation, particularly in the brain, is believed to contribute to many of the neurological side effects of chemotherapy in humans, such as depression, anxiety and short-term memory loss.
“Timing of drug administration can have a big effect on inflammation, and that may potentially affect a wide variety of harmful side effects,” said Courtney DeVries, co-author of the study and professor of neuroscience at The Ohio State University’s Wexner Medical Center.
But the results also showed an important complicating factor: The inflammatory effects were opposite in the brain versus the spleen depending on the time the drugs were given.
“The spleen and the brain were out of phase. When inflammation was high in one, it was low in the other,” said co-author Randy Nelson, also a professor of neuroscience at Ohio State’s Wexner Medical Center.
The study was published in the journal Scientific Reports.
These results mark another step in how scientists understand cancer chronotherapy – using the body’s daily circadian rhythms to time treatments so they are most effective and have the fewest side effects.
“I think we know enough about circadian rhythms in terms of physiology that we can start translating these findings into medical research and practice in humans,” Nelson said.
The research team studied the drugs cyclophosphamide and doxorubicin, a common treatment for breast cancer, in female mice. The mice did not have tumors because this study was designed just to look at the inflammatory response to the drugs.
The mice were injected with the drugs two hours after daylight (which is their inactive period) or two hours after lights were turned off (their active period).
Researchers collected tissue and checked for signs of inflammation in the spleen, an important immune system organ. The also looked at two sites in the brain: the hypothalamus and the hippocampus. Tissue was collected at 1, 3, 9 or 24 hours after the injection.
Results showed that injecting mice with the chemotherapy drugs in their inactive phase (daylight) increased the expression of genes that promoted inflammation within the spleen. The researchers found increased production of two toxic drug metabolites, products of the chemo drugs. These metabolites are related to inflammation and one of them, doxorubicinol, causes heart damage in some patients.
“The timing of when patients receive drugs has the potential to reduce serious side effects,” DeVries said.
The effect was different for mice that received the drugs two hours after the lights were out. In these mice, inflammation measured in the spleen was much lower than the mice injected during the day.
The pattern was reversed in the brain, however. Mice injected at night had increases in pro-inflammatory gene expression, but showed less evidence of inflammation when injected during the day.
The difference in inflammation response between the brain and the rest of the body needs to be better appreciated by physicians, Nelson said.
“Many times physicians measure markers of inflammation in the blood and assume that is what is happening in the brain, but we found that just the opposite is happening,” he said.
Why is there a difference between how the brain and spleen are reacting to these chemotherapy drugs?
Other research has shown that the clock genes in the brain are out of sync with those in other organs. Expression of these clock genes may affect how the drugs are processed, or metabolized, in the body, Nelson said.
These findings can’t tell us the best time to administer chemotherapy drugs in humans, DeVries said of the new study.
“But it does demonstrate that time of day is an important factor that needs to be considered in when the drugs are given,” she said.
Nelson noted that this study only looked at administering drugs at two time points.
“There may be a sweet spot that maximizes the efficacy of the drugs and minimizes the side effects. We don’t know that yet.”
The National Institutes of Health provided funding for the study.
Other members of the research team, all from Ohio State, were Jeremy Borniger, William Walker, Monica Gaudier-Diaz, Curtis Stegman, Ning Zhang and Jennifer Hollyfield.
Genetic factor to colon cancer
One of the biggest cancer culprits in the United States is colorectal cancer, with 400 new diagnoses each day. As a result, it’s the second most common cancer that affects both men and women.
A recent study published in JAMA Oncology from The Ohio State University Comprehensive Cancer Center shows there’s a hidden genetic factor to many colorectal cancer diagnoses that most patients don’t even realize they have – it’s called Lynch syndrome.
Like BRCA is to breast cancer, Lynch syndrome is passed down genetically through families and dramatically increases a person’s risk for colorectal cancer. The Ohio State study tested more than 3,000 newly-diagnosed colorectal cancer patients and their at-risk family members for Lynch syndrome and found that 95% of those affected didn’t know they had it.
“One of the keys to beating many types of cancer is catching it early, and the best way to do that is to know a patient’s risk so we can monitor them closely and treat them at the first sign of trouble,” said Heather Hampel, MS, LGC, principal investigator of Ohio Colorectal Cancer Prevention Initiative and licensed genetic counselor at The Ohio State University Comprehensive Cancer Center.
Through early detection of the condition, Hampel and her team of researchers estimate 639 years of life will be saved.
OSU first in U.S. to test new heart treatment
A Whitehall, Ohio man is the first in the U.S. to undergo a brand new treatment designed to remove excess fluid from hospitalized patients suffering from congestive heart failure, which affects six million Americans. The trial procedure occurred last week (March 2) at The Ohio State University Richard M. Ross Heart Hospital.
Ohio State cardiovascular researchers are testing the safety and feasibility of inserting a special catheter to improve the flow of fluid from the lymphatic system. Lymphatic vessels help remove fluid from tissues and return it to the body’s circulatory system. Excess fluid is then eliminated by the kidneys. The lymphatic system typically drains up to two gallons of fluid per day. In acute congestive heart failure, this process is impeded, allowing fluid build-up, or edema, to occur in the lungs and other areas of the body. Edema is a major symptom in heart failure, and this novel therapy aims to treat one of the underlying causes.
Ohio State is first to conduct the procedure and is one of only two test sites in the U.S., along with Advocate Christ Hospital in Chicago.
“Most of the recent advancements in heart failure have been for non-hospitalized patients, to help keep them well,” said Dr. Sitaramesh Emani, a cardiologist and director of heart failure clinical research at Ohio State, who performed the procedure. “We need new therapies for patients once they’ve become hospitalized. There hasn’t been a lot of new development there.”
Raynes Rozzelle, 61, has lived with various heart issues most of his life – from a heart murmur, to an irregular heartbeat, and then a heart attack four years ago. He’s been in and out of the hospital with congestive heart failure for about a year. He says he readily agreed to try something new.
“I thought, not only could this possibly help me, it may end up helping a lot of other people. I was raised to help others whenever you can,” Rozzelle said.
The treatment, developed by WhiteSwell Medical, is the first known catheter specifically designed to target the lymphatic system internally. The device is placed in the neck under ultrasound guidance in the catheterization lab, and the treatment continues at the bedside using a machine that helps circulate some of the blood.
Currently, in-hospital treatment for congestive heart failure involves removing excess fluid with diuretic medication and/or ultrafiltration, in which a machine bypasses the kidneys and filters water and salt from the body. However, the treatments can have unwanted side effects such as low blood pressure and worsening kidney function.
“In some cases, the diuretics provide only partial relief, so there’s a need for new options for treating the congestion associated with heart failure,” said Dr. Garrie Haas, lead investigator on the study and director of the Ohio State advanced heart failure program. “More efficient and effective treatment not only improves the patient’s quality of life, it can reduce re-hospitalizations, so we’re interested in trying this new approach.”
According to the Centers for Disease Control, heart failure is the most common reason for hospital admission in those ages 65 and older, and it accounts for one million admissions each year in the U.S.
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