The cognitive side effects that plague many cancer patients after chemotherapy are likely due to progressive, delayed damage to myelin and to gene expression changes that prevent myelin repair by devastating the pool of oligodendrocyte precursors in the CNS, reported Ruolan Han, PhD, and colleagues in the April 22 online Journal of Biology. The result is a progressive collapse in the efficiency of neural conduction in the CNS.
“Chemo brain,” a term commonly used to refer to these cognitive side effects, is characterized by short-term memory loss and, in extreme cases, seizures, vision loss, and even dementia. It often appears weeks or months after completion of cancer treatment. More than 82% of breast cancer patients report some form of cognitive impairment, and up to 20% have lingering cognitive problems years after treatment. These effects were often attributed to fatigue, depression, anxiety, or immunologic or vascular changes.
To explore the underlying pathogenic mechanisms of cognitive decline following chemotherapy, the researchers conducted animal studies with 5-fluorouracil (5-FU) at doses widely used in cancer treatment. They found myelin damage and changes in neural conduction that constitute a previously unrecognized class of chemotoxicity.
“Systemic 5-FU exposure was sufficient to cause substantial delayed abnormalities in oligodendrocyte biology, in regard to both transcriptional regulation and maintenance of myelin integrity,” said coauthor Mark Noble, PhD, Director of the University of Rochester Stem Cell and Regenerative Medicine Institute in New York. “It is also important to note that our studies demonstrate that there is no requirement for an ongoing disease process in order for such damage to occur, nor is it necessary to use combinations of agents.... Thus, it is clear that this damage is a direct consequence of treatment with chemotherapy,” he continued.
“These data fundamentally change our understanding of the neurologic damage done by systemic treatment with chemotherapy in multiple ways,” Dr. Noble told Neurology Reviews. “It is quite intriguing that the same cells are vulnerable to 5-FU, cisplatin, carmustine (bacteria-controlled nursing unit), and cytarabine, suggesting these agents may be killing normal CNS cells by a mechanism distinct from the mechanisms studied in cancer cells.”
The myelin abnormalities appear to be related to dysregulation of Olig2 gene expression in oligodendrocytes, resulting in “scattered foci of demyelinated axons, including partial or complete loss of myelin sheaths and increases in interlaminar splitting of the myelin sheaths,” said the researchers. This led, at six months posttreatment, to reduced cellularity and loss of myelin basic protein in animal models.
A series of experiments on neural progenitor cells and oligodendrocytes showed that both are vulnerable to clinically relevant levels of 5-FU. Exposure at the low end of concentrations observed in the CSF of 5-FU–treated cancer patients caused a 55% to 70% reduction in the viability of dividing oligodendrocyte-type-2 astrocyte progenitor cells (O-2A/OPCs) and also of nondividing oligodendrocytes. Longer exposure killed progressively more cells, at doses that had no effect on a variety of cancer cell lines.
Toxicity not only caused cell death but also was associated with suppression of O-2A/OPC division, even with transient exposure “at levels that represent small fractions of the CNS concentrations achieved during cancer treatment,” said the researchers. This suppression of progenitor cells contributed to a progressive collapse of myelin-forming cell populations in the CNS.
“The findings that oligodendrocytes and progenitor cells are targets, and that we see such extensive damage of the white matter, greatly strengthens the view that alterations in conduction (ie, the outcome of myelin damage) are contributors to cognitive/neurologic problems in these patients,” said Dr. Noble.
To determine whether 5-FU exposure was associated with functional impairment, the researchers tested hearing in treated animals at various time points after exposure.
“Our analysis of auditory function in 5-FU treated animals revealed what seems to be a previously unrecognized consequence of chemotherapy exposure: increased latencies of impulse transmission,” the investigators reported. The delays in nerve impulse transmission were large enough to be considered “highly significant” functional changes.
The researchers suggest that the type of auditory function analysis used in these studies provides a noninvasive functional analysis of myelination-related outcomes and could be readily done in humans.
5-FU toxicity occurred at or below clinically relevant exposure levels and affected both lineage-restricted progenitor cells of the CNS and nondividing oligodendrocytes. This was surprising, said Dr. Noble, since 5-FU had been thought to target dividing cells specifically; oligodendrocytes do not divide in the conditions used in these experiments.
“The transcriptional findings are, to my knowledge, quite novel in showing that damage may be much more subtle than simple perturbations of the cell death and cell division. We are now looking to see how extensively transcriptional regulation is altered by these agents,” Dr. Noble said.