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Cognitive Damage May Appear After Cancer Treatment Ends

Damage to central nervous system cells occurs following chemotherapy, even when the brain is not the target for the treatment.

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 deficits.

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.

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"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 long-lasting effect.

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 problems."

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 problems."

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 deficits.

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 oligodendrocytes.

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 consistently performed."

Noble and others say these results do not rule out chemotherapy for the foreseeable future.

"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 available.

"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>.

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