For many cancer patients, chemotherapy can be a debilitating experience,
one in which they lose their hair and, some may swear, their minds.
The effects of radiation treatment for central nervous system tumors on
cognitive skills is well known, but a new study documents on the cellular
level what many have observed—that systemic chemotherapy causes similar
A series of in vitro and in vivo experiments shows that some chemotherapy
drugs damage neural progenitor cells and oligodendrocytes in the central
nervous system more than they harm cancer cells, which may explain why many
cancer patients have cognitive problems following treatment.
Mark Noble, Ph.D., Margot Mayer-Pröschel, Ph.D., and three colleagues
from the University of Rochester Medical Center's Department of Biomedical
Genetics, tested three widely used chemotherapeutic agents associated with
central nervous system toxicity—carmustine (also referred to as BCNU),
cisplatin, and cytosine arabinoside (cytarabine)—on rat and human cells
in vitro, and on mice.FIG1
"The vulnerability of multiple normal cell populations of the CNS to
cisplatin, BCNU, and cytarabine rivals the vulnerability of cancer cells
themselves," they wrote in an article in the online Journal of
Biology. Progenitor cells seem to be more affected than stem cells, they
said. Cell division declined even after treatment ended, indicating a
Despite the evidence for neurological and cognitive deficits, there is an
absence of biological explanations of why they occur, although there are
diseases in which dysfunctions of precursor cells is the source of the
illness, Noble told Psychiatric News.
"Being diagnosed with cancer and then getting treated are pretty
stressful times for patients, so it's no surprise that people develop acute
cognitive problems," said Timothy Ahles, Ph.D., of the Department of
Psychiatry and Behavioral Sciences at Memorial Sloan Kettering Cancer Center
in New York. "Those cognitive symptoms usually improve following
chemotherapy treatment, but perhaps 20 percent have ongoing
Chemotherapeutic agents in contact with CNS cells can cause neurotoxicity,
but Noble's study shows that damage can be caused by chemotherapy given
systemically, said Ahles in an interview. "We used to think that chemo
drugs couldn't cross the blood-brain barrier, or at least not in significant
amounts. But if adjuvant chemotherapy can cause cognitive problems even if
they don't get into the CNS, then maybe it doesn't take that much to cause
Even though a majority of cancer patients don't experience these long-term
cognitive effects, oncologists can't predict who will and who won't. Side
effects tend to be subtle, said Ahles. Patients might have trouble
concentrating or processing information but it wouldn't be dramatic as with
Alzheimer's or head trauma. They and their families might notice, but an
outside observer wouldn't. The patient's social setting is important, too. A
retiree might not have too many problems coping, but an active, working,
middle-aged adult might have lots of demands that would expose cognitive
One problem in studying the cognitive effects of chemotherapy is that
complaints arise after treatment, but little prediagnostic information is
available about patients, said Ann O'Mara, Ph.D., program director in the
Division of Cancer Prevention at the National Cancer Institute. Once patients
are diagnosed, stress and anxiety about their condition complicate
neuropsychiatric measurements. In addition, those measures have not been
standardized until recently, although some clinical trials networks are now
routinely giving neuropsychiatric tests, she said.
Noble and colleagues dosed neuroepithelial stem cells, neural-restricted
precursor cells, glial-restricted precursor cells, oligodendrocyte precursor
cells, and several human cancer cell lines with BCNU and cisplatin in vitro.
Exposing oligodendrocyte precursor cells to cisplatin and BCNU reduced cell
division and increased differentiation into oligodendrocytes. Cytarabine was
similarly toxic to neural progenitor cells, even though it has a different
mechanism of action than the other two drugs.
In another experiment, the researchers treated mice with BCNU and cisplatin
and noted adverse effects in neuronal and glial precursor cells and
The effects observed appear to be different from the usual chemotherapy
side effects, like hair loss, in that they affect oligodendrocytes that are
not dividing, so the drugs act in ways other than interfering with cell
division, said Noble. He is not certain why this occurs, but possible
explanations may involve mitochondrial division or some novel regulatory
pathway involving oxidative stress.
How the drugs cross the blood-brain barrier is another question, he said."
In chemotherapeutic agents, you're looking for `tissue penetrability,'
which usually means lipophilic, but that makes it easier to cross the
blood-brain barrier. So, paradoxically, it means you have to look for a less
lipophilic compound to reduce the cognitive effects."
Noble and his colleagues did not stumble onto these experiments by
accident. They spent years working out the medium and the growth factors to
develop in vitro models that would match results in vivo, he said. "We
can put precursor cells in a Petri dish, and they will produce
oligodendrocytes like the ones in an animal."
This similarity of effects opens avenues to more research with some
assurance that results obtained in vitro will be applicable to living
organisms. The techniques might also help find less toxic cancer therapies, if
applied early in the drug-discovery process.
However, Noble and his colleagues wrote, "it will be of particular
importance to include more profound analysis of CNS toxicity in the assessment
of new candidate chemotherapeutic drugs, an evaluation that currently is not
Noble and others say these results do not rule out chemotherapy for the
"The state of the science is not advanced enough to support an
informed decision about the patient's care," said Ahles. "Not
treating their cancer is not a choice."
Instead, cognitive-behavioral therapy and compensation strategies like
making lists and getting organized can help patients now, he said. Studies of
psycho-stimulants and gingko biloba are under way, but results are not
"The whole field is really in its infancy," said Ahles."
Only since the mid-1990s has there been any serious research. We're
still trying to sort out the extent of the problem, what treatments cause it
and how they work."
"CNS Progenitor Cells and Oligodendrocytes Are Targets of
Chemotherapeutic Agents in Vitro and in Vivo" is posted at<http://jbiol.com/content/5/7/22>.▪