CT causes delayed CNS damage

Although the lack of specificity of chemotherapy (CT) has always been a limiting factor in its use, patients' brains were thought to be offered some protection by the blood-brain barrier. However, it is becoming increasingly recognised that many CT agents can affect brain function by both direct and indirect methods.

Now, research published in the 22nd April edition of the Journal of Biology (2008;7:12) has demonstrated that treatment with a single CT agent, 5-FU, by itself is sufficient to cause a syndrome of delayed degeneration in the central nervous system (CNS). The drug is a widely used CT agent that is administered, alone or in combination with other agents, in the treatment of cancers of the colon, rectum, breast, stomach, pancreas, ovaries and bladder.

Surprisingly, little is known about the side effects of CT on the CNS, despite the obvious clinical importance. Until now, researchers have not fully understood the underlying biology, including whether these effects require: exposure to multiple CT agents; CT agents plus the body's own response to cancer; blood-brain barrier damage; or inflammation.

In the new work, Professor Mark Noble and colleagues from the University of Rochester Stem Cell and Regenerative Medicine Institute and Harvard Medical School discovered that short-term systemic administration of 5-FU to mice caused both acute CNS damage and a syndrome of progressively worsening delayed damage. This damage was not self-repairing, and instead became worse over time. In addition, the scientists demonstrated that treatment with CT also had delayed effects on the speed with which information is transferred from the ear to the brain.

Noble commented: "Multiple clinical reports have identified neurotoxicity as a complication of treatment regimens in which chemotherapeutic agents such as 5-fluorouracil are components. As treatments with chemotherapeutic agents will clearly remain the standard of care for cancer patients for many years to come, the need to better understand such damage is great."

One key finding of the study was that clinically-relevant concentrations of 5-FU were toxic not only for dividing cells of the CNS but also for the cells that produce the insulating myelin sheaths, called non-dividing oligodendrocytes. The delayed damage the researchers measured was to the myelinated tracts of the CNS and associated with extensive myelin pathology. The findings regarding the speed of ear-to-brain information transfer may offer a non-invasive means of analysing myelin damage associated with cancer treatment.

The research provides the first demonstration that delayed CNS damage can be induced by a single CT agent and also generates the first animal model of such damage. These studies further demonstrate that this syndrome differs from that caused by irradiation and thus may represent a new class of delayed CNS degenerative damage. Previous studies have linked various CT agents, including methotrexate, cyclophosphamide, adriamycin and cisplatin, with impaired cognitive function, although results have been variable. This new work is consistent with the clinical syndrome that is commonly observed in patients and will hopefully guide future studies into the mechanisms of acute and delayed injury to the brain from clinically-relevant exposure to CT agents.

Matthew Dennis - Editor, Cancer Drug, News