Curbing the pain of chemotherapy

Effective in animal model, vitamin B3 might help cancer patients

By Jennifer Brown

Chemotherapies have improved cancer survival rates, but many of these drugs also cause debilitating side effects that decrease the quality of life of patients and survivors. In particular, many anti-cancer drugs cause chemotherapyinduced peripheral neuropathy (CIPN)—nerve damage and pain.

A new study in rats suggests that nicotinamide riboside (NR), a form of vitamin B3, may be useful for treating or preventing CIPN. The findings by researchers at the University of Iowa lay the groundwork for testing whether this nutritional supplement can reduce nerve pain in cancer patients receiving chemotherapy.

“Chemotherapy-induced peripheral neuropathy can both hinder continuation of treatment and persist long after treatment has ended, severely affecting the quality of life of cancer patients,” says Marta Hamity, PhD, UI assistant research scientist and first author on the study published in the May 2017 issue of the Journal of the International Association for the Study of Pain.

“Our findings support the idea that NR could potentially be used to prevent or mitigate CIPN in cancer patients, resulting in a meaningful improvement in their quality of life and the ability to sustain better and longer treatment,” Hamity says.

A report from the American Society for Clinical Oncology states that there is an unmet need for treatments that can alleviate CIPN.

The UI study, led by Hamity and Donna Hammond, PhD, UI professor of anesthesia and pharmacology at the UI Carver College of Medicine, tested the effect of NR in female rats that were treated with paclitaxel, a chemotherapy commonly used to treat breast and ovarian cancer. Paclitaxel, when given at doses that mimicked the amount a human patient would receive, caused peripheral neuropathy in the rats, and the effects lasted at least five weeks beyond the end of the chemotherapy treatment.

The team used a standard test to assess the pain caused by CIPN. They measured the rats’ increased sensitivity to a light foot poke. Untreated rats did not withdraw their foot when light pressure was applied. However, treatment with paclitaxel made the rats hypersensitive to this light touch and caused them to withdraw their foot.

NR boosts levels of an important cell metabolite called nicotinamide adenine dinucleotide (NAD+). Previous animal studies, including work from the UI lab of study co-author Charles Brenner, PhD, department executive officer of biochemistry, have shown that increasing NAD+ levels with NR can protect against many types of nerve damage. The new study found that the NR supplement increased levels of NAD+ in the rats’ blood by about 50 percent.

Prophylactic treatment with daily doses of NR (200 mg/kg) for seven days before chemotherapy and maintained for 24 days after ceasing chemotherapy prevented the hypersensitivity to touch in the rats. This protective effect lasted for at least two weeks after the NR supplementation stopped.

By nature, rats prefer the dark. The team found that untreated rats tolerated many pokes in a dark environment before they were prompted to move to a brightly lit environment. In contrast, rats with CIPN would leave the dark chamber after fewer pokes and would remain in the light. Rats getting both chemotherapy and the NR supplement behaved more like untreated rats and tolerated more poking before leaving the dark.

“The touch-sensitivity test measures the threshold where a light touch that normally is not painful is now perceived as painful because of the neuropathy. For example, people with CIPN can find the light touch of clothes or typing on a keyboard painful,” Hamity explains. “In the case of the ‘escape’ test, we were trying to mimic how unpleasant a normal stimulus can be because of the neuropathy—and if that would cause you to avoid (that stimulus) even if it means choosing an activity that you don’t enjoy. For example, typing can become so painful that you avoid doing it even if it means not being able to work.”

When the researchers began NR supplementation 14 days after the chemotherapy treatment, it reversed touch hypersensitivity in some, but not all, of the rats. However, it was still able to reduce the “escape” behavior in all of the animals.

The study is the first to measure this behavioral impact of CIPN, as well as hypersensitivity to touch. Measuring the effect of potential therapies on both dimensions of pain perception may provide better preclinical information that can lead to more successful clinical trials. The study also is among the first to use female rats to investigate CIPN.

Hammond is encouraged by the study findings but cautious about what they may mean for human therapies.

“The preclinical literature is rife with drugs that alleviate chemotherapy-induced peripheral neuropathy but that fail to do so under rigorous clinical testing,” says Hammond, who also is diirector of the Pain Research Program and a member of Holden Comprehensive Cancer Center at the UI. “We believe we are using a model that is more clinically relevant—but the true test of that will not be made until the clinical trial is done.”

Bedside-to-bench approach drives study

By Tony Craine

Because so many previous attempts at treatments for chemotherapy-induced peripheral neuropathy (CIPN) have fallen short in clinical testing, the authors of a University of Iowa study were determined to design their experiments to be as clinically relevant as possible.

Marta Hamity’s visits with patients in the infusion suite helped her design a study focused on treatments for pain caused by chemotherapy drugs.

Lead author Marta Hamity, PhD—with encouragement from her mentor and co-author Donna Hammond, PhD—visited Holden Comprehensive Cancer Center at the UI during the design phase of the study. Hamity shadowed oncologist Alexandra Thomas, MD, so she could hear CIPN stories straight from patients, including a woman who asked if a November chemotherapy session could be delayed.

“She wanted to be able to cook her family a big Thanksgiving dinner, but after each treatment she felt like her feet and hands were on fire, making it very difficult for her to do her daily chores,” Hamity says. “Those stories were a big motivation for us to try to design behavioral experiments with our rodent model that would mimic how CIPN affects quality of life. It also made us understand that even small relief of the neuropathy could greatly improve daily life.”

Hamity says Holden Comprehensive Cancer Center is taking steps to encourage more of this type of bedside-to-bench research.

“People are realizing that you can really improve your research and provide better treatments if basic scientists and MDs interact more often,” she says. “As much as I could learn in the literature, listening to patients and their doctors provided me with a much deeper understanding of how CIPN can hinder not only the capability of receiving the best course of treatment but also the overall quality of life of patients.”

Along with patient experiences, feedback from doctors helped the researchers refine their approach and make their experiments with a rodent model more clinically relevant, Hamity says.

“One of the great advantages of doing basic research at the University of Iowa is the possibility to work side by side with a physician,” Hamity says. “I hope more basic researchers get the chance to benefit from interacting with the great medical team at the university.”