Chemotherapy Causes Delayed Severe Neural Damage, Study Shows
ScienceDaily (Apr. 22, 2008) — Cancer treatment with chemotherapeutic agents is often associated with delayed adverse neurological consequences - an occurrence often referred to as "chemobrain" - that may compromise the quality of life of a proportion of cancer survivors. Now, new research demonstrates that treatment with a single chemotherapeutic agent, 5-fluorouracil (5-FU), by itself is sufficient to cause a syndrome of delayed degeneration in the central nervous system (CNS). 5-FU is a widely used chemotherapeutic agent that is employed, alone or in combination with other agents, in the treatment of cancers of the colon, rectum, breast, stomach, pancreas, ovaries and bladder.
Little is known about the side-effects of chemotherapy on the CNS, despite their obvious clinical importance. Until now researchers have not fully understood the underlying biology, including whether these effects require: exposure to multiple chemotherapeutic agents; chemotherapeutic agents plus the body's own response to cancer; blood-brain barrier damage; or inflammation. Clinicians have also lacked animal models to study this important problem.
Professor Mark Noble and colleagues of the University of Rochester Stem Cell and Regenerative Medicine Institute and the Harvard Medical School, Boston discovered that short-term systemic administration of 5-FU to mice caused both acute CNS damage and a syndrome of progressively worsening delayed damage. This damage was not self-repairing, and instead became worse over time. In addition, Noble and colleagues also demonstrated that treatment with chemotherapy also had delayed effects on the speed with which information is transferred from the ear to the brain.
Myelin sheaths are necessary for normal neuronal function. One key finding of the study was that clinically relevant concentrations of 5-FU were toxic not only for dividing cells of the CNS but also for the cells that produce the insulating myelin sheaths (non-dividing oligodendrocytes). The delayed damage the researchers measured was to the myelinated tracts of the CNS and associated with extensive myelin pathology. The findings regarding the speed of ear-to-brain information transfer may offer a non-invasive means of analyzing myelin damage associated with cancer treatment.
"Multiple clinical reports have identified neurotoxicity as a complication of treatment regimens in which chemotherapeutic agents such as 5-fluorouracil are components," says Noble. "As treatments with chemotherapeutic agents will clearly remain the standard of care for cancer patients for many years to come, the need to better understand such damage is great."
Professor Noble continues "These studies extend the field of stem cell medicine beyond the use of cell transplantation for tissue repair. It is our knowledge of stem cell biology that allows us to begin to understand some of the causes of this syndrome, as well as providing the means of preventing or repairing this damage."
This research provides the first demonstration that delayed CNS damage can be induced by a single chemotherapeutic agent and also generates the first animal model of such damage. These studies further demonstrate that this syndrome differs from that caused by irradiation and thus may represent a new class of delayed CNS degenerative damage.
Journal reference: Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the CNS. Ruolan Han, Yin M. Yang, Joerg Dietrich, Anne Luebke, Margot Mayer-Pröschel and Mark Noble. Journal of Biology (in press)
Adapted from materials provided by BioMed Central/Journal of Biology, via EurekAlert!, a service of AAAS.
BioMed Central/Journal of Biology (2008, April 22). Chemotherapy Causes Delayed Severe Neural Damage, Study Shows. ScienceDaily. Retrieved April 23, 2008, from http://www.sciencedaily.com /releases/2008/04/080421191425.htm
Chemotherapy's Damage To The Brain Detailed
While it is increasingly acknowledged by the scientific community that many chemotherapy agents may have a negative impact on brain function in a subset of cancer patients, the precise mechanisms that underlie this dysfunction have not been identified. (Credit: iStockphoto/Vasiliy Yakobchuk)ScienceDaily (Apr. 22, 2008) — A commonly used chemotherapy drug causes healthy brain cells to die off long after treatment has ended and may be one of the underlying biological causes of the cognitive side effects -- or "chemo brain" -- that many cancer patients experience. That is the conclusion of a study published today in the Journal of Biology.
A team of researchers at the University of Rochester Medical Center (URMC) and Harvard Medical School have linked the widely used chemotherapy drug 5-fluorouracil (5-FU) to a progressing collapse of populations of stem cells and their progeny in the central nervous system.
"This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function," said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. "Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients."
Cancer patients have long complained of neurological side effects such as short-term memory loss and, in extreme cases, seizures, vision loss, and even dementia. Until very recently, these cognitive side effects were often dismissed as the byproduct of fatigue, depression, and anxiety related to cancer diagnosis and treatment. Now a growing body of evidence has documented the scope of these conditions, collectively referred to as chemo brain. And while it is increasingly acknowledged by the scientific community that many chemotherapy agents may have a negative impact on brain function in a subset of cancer patients, the precise mechanisms that underlie this dysfunction have not been identified.
Virtually all cancer survivors experience short-term memory loss and difficulty concentrating during and shortly after treatment. A study two years ago by researchers with the James P. Wilmot Cancer Center at the University of Rochester showed that upwards of 82% of breast cancer patients reported that they suffer from some form of cognitive impairment.
While these effects tend to wear off over time, a subset of patients, particularly those who have been administered high doses of chemotherapy, begin to experience these cognitive side effects months or longer after treatment has ceased and the drugs have long since departed their systems. For example, a recent study estimates that somewhere between 15 and 20 percent of the nation's 2.4 million female breast cancer survivors have lingering cognitive problems years after treatment. Another study showed that 50 percent of women had not recovered their previous level of cognitive function one year after treatment.
Two years ago, Noble and his team showed that three common chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat. While these experiments were among the first to establish a biological basis for the acute onset of chemo brain, they did not explain the lingering impact that many patients experience.
The scientists conducted a similar series of experiments in which they exposed both individual cell populations and mice to doses of 5-fluorouracil (5-FU) in amounts comparable to those used in cancer patients. 5-FU is among a class of drugs called antimetabolites that block cell division and has been used in cancer treatment for more than 40 years. The drug, which is often administered in a "cocktail" with other chemotherapy drugs, is currently used to treat breast, ovarian, stomach, colon, pancreatic and other forms of cancer.
The researchers discovered that months after exposure, specific populations of cells in the central nervous -- oligodendrocytes and dividing precursor cells from which they are generated -- underwent such extensive damage that, after 6 months, these cells had all but disappeared in the mice.
Oligodendrocytes play an important role in the central nervous system and are responsible for producing myelin, the fatty substance that, like insulation on electrical wires, coats nerve cells and enables signals between cells to be transmitted rapidly and efficiently. The myelin membranes are constantly being turned over, and without a healthy population of oligodendrocytes, the membranes cannot be renewed and eventually break down, resulting in a disruption of normal impulse transmission between nerve cells.
These findings parallel observations in studies of cancer survivors with cognitive difficulties. MRI scans of these patients' brains revealed a condition similar to leukoencephalopathy. This demyelination -- or the loss of white matter -- can be associated with multiple neurological problems.
"It is clear that, in some patients, chemotherapy appears to trigger a degenerative condition in the central nervous system," said Noble. "Because these treatments will clearly remain the standard of care for many years to come, it is critical that we understand their precise impact on the central nervous system, and then use this knowledge as the basis for discovering means of preventing such side effects."
Noble points out that not all cancer patients experience these cognitive difficulties, and determining why some patients are more vulnerable may be an important step in developing new ways to prevent these side effects. Because of this study, researchers now have a model which, for the first time, allows scientists to begin to examine this condition in a systematic manner.
Other investigators participating in the study include Ruolan Han, Ph.D., Yin M. Yang, M.D., Anne Luebke, Ph.D., Margot Mayer-Proschel, Ph.D., all with URMC, and Joerg Dietrich, M.D., Ph.D., formerly with URMC and now with Harvard Medical School. The study was funded by the National Institutes of Neurological Disorders and Stroke, the Komen Foundation for the Cure, and the Wilmot Cancer Center.
Adapted from materials provided by University of Rochester Medical Center.
University of Rochester Medical Center (2008, April 22). Chemotherapy's Damage To The Brain Detailed. ScienceDaily. Retrieved April 23, 2008, from http://www.sciencedaily.com /releases/2008/04/080422103947.htm