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 percent 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 percent 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 six
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.
For more media inquiries, contact:
Mark Michaud
mark_michaud@urmc.rochester.edu
http://www.urmc.rochester.edu/pr/news/story.cfm?id=1963