Chemotherapy Damages the Brain

[Guest guest]

*Researchers Detail Chemotherapy's Damage to the Brain

 

*University of Rochester Medical Center

http://www.urmc.rochester.edu/pr/news/story.cfm?id=1963

 

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

(585) 273-4790

mark_michaud