Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system.
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.
Han
Ruolan
R
Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Elmwood Avenue, Rochester, NY 14642, USA. ruolan_han@urmc.rochester.edu
Yang
Yin M
YM
Dietrich
Joerg
J
Luebke
Anne
A
Mayer-Pröschel
Margot
M
Noble
Mark
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001306:Auditory Pathways / Q000187:drug effects; D001973:Bromodeoxyuridine; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology; D005472:Fluorouracil / Q000009:adverse effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009186:Myelin Sheath / Q000187:drug effects* / Q000648:ultrastructure; D051381:Rats; D013234:Stem Cells; D013778:Tetrazolium Salts; D013844:Thiazoles
D000970:Antineoplastic Agents; D007211:Indoles; D013778:Tetrazolium Salts; D013844:Thiazoles; C007293:DAPI; C022616:thiazolyl blue; D001973:Bromodeoxyuridine; D005472:Fluorouracil