A new study says that cancer patients who complain of memory and other cognitive problems after having chemotherapy have scientific evidence to back up their claims.
The research concludes that a common chemotherapy drug, known as 5-fluorouracil (5-FU), causes stem cells in the central nervous system to die off well after treatment has ended. The resulting side effects are often referred to as "chemo brain."
"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," senior study author Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute, said in a statement.
The study was conducted by researchers at the University of Rochester Medical Centre (URMC) and Harvard Medical School and was published Monday in the Journal of Biology.
After having chemotherapy, many cancer patients complain of having symptoms ranging from short-term memory loss to, in some rare cases, seizures, vision loss and dementia. Recent studies are starting to point to the fact that these symptoms are indeed a result of impaired biological processes and not just a result of the fatigue and stress associated with cancer treatment.
The 5-FU chemotherapy drug treats cancer by halting cell division, and has been used for more than 40 years. It is often given in combination with other chemotherapy drugs, and is commonly used to treat breast, ovarian, stomach, colon, pancreatic and other types of cancer.
In this study, the researchers found that cells in the nervous system known as oligodendrocytes were severely damaged when exposed to levels of 5-FU common in cancer treatment.
Oligodendrocytes produce myelin, the fatty substance that coats nerve cells, enabling signals to be sent rapidly between cells. Myelin membranes turn over quite rapidly, but without oligodendrocytes, they break down, disrupting transmission of the messages.
"It is clear that, in some patients, chemotherapy appears to trigger a degenerative condition in the central nervous system," Noble added in his statement.
"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."
Researchers say that because not all cancer patients develop cognitive problems, the next avenue of study should be why chemotherapy so negatively affects some and not others.
Abstract:
Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system
Ruolan Han, Yin M Yang, Joerg Dietrich, Anne Luebke, Margot Mayer-Pr�schel and Mark Noble
Background: Cancer treatment with a variety of chemotherapeutic agents often is associated with delayed adverse neurological consequences. Despite their clinical importance, almost nothing is known about the basis for such effects. It is not even known whether the occurrence of delayed adverse effects requires exposure to multiple chemotherapeutic agents, the presence of both chemotherapeutic agents and the body's own response to cancer, prolonged damage to the blood-brain barrier, inflammation or other such changes. Nor are there any animal models that could enable the study of this important problem.
Results: We found that clinically relevant concentrations of 5-fluorouracil (5-FU; a widely used chemotherapeutic agent) were toxic for both central nervous system (CNS) progenitor cells and non-dividing oligodendrocytes in vitro and in vivo. Short-term systemic administration of 5-FU caused both acute CNS damage and a syndrome of progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology. Functional analysis also provided the first demonstration of delayed effects of chemotherapy on the latency of impulse conduction in the auditory system, offering the possibility of non-invasive analysis of myelin damage associated with cancer treatment.
Conclusions: Our studies demonstrate that systemic treatment with a single chemotherapeutic agent, 5-FU, is sufficient to cause a syndrome of delayed CNS damage and provide the first animal model of delayed damage to white-matter tracts of individuals treated with systemic chemotherapy. Unlike that caused by local irradiation, the degeneration caused by 5-FU treatment did not correlate with either chronic inflammation or extensive vascular damage and appears to represent a new class of delayed degenerative damage in the CNS.
