Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system

Abstract

BackgroundCancer 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.ResultsWe 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.ConclusionsOur 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.

Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy

“…Since both cyclophosphamide and 5-fluorouracil continue to be implemented in current regimens, and these agents, as well as many other commonly used agents are independently associated with structural brain changes in animals [24,25], our study results might also apply to contemporary regimens.…”

Handing Off Critically Ill Patients to Family Caregivers

“…Although these share in common some relative or absolute loss of one or more functional abilities and/or the need for management of one or more persisting health problems, the onset of these impairments may be slow (eg, Alzheimer's disease, other dementias, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis) 11 or delayed (some brain tumors, sequelae following traumatic brain injury or blast injuries such as improvised explosive device detonation, or toxic complication associated with some chemotherapeutic agents such as 5-fluorouracil, 12 or immediate (eg, stroke, gunshot injury to the head, spinal cord injury).…”

Déficits neuropsicológicos asociados a alteraciones cerebrales secundarias a tratamiento oncológicos

“…En el área infantil, la supervivencia en niños con tumores cerebrales se ha incrementado en los últimos 20 años pero, desafortunadamente, esas terapias empleadas sobre el sistema nervioso central en niños, particularmente la radiación, se asocian al desarrollo en ellos de problemas de aprendizaje, leucoencefalopatía, endocrinopatías y oncogénesis (65) . La leucoencefalopatía en niños con leucemia linfoblástica se manifiesta en letargia, ataques de corte epiléptico, problemas del lenguaje, ataxia y pérdida de memoria (66) . Bernabeu et al (2003), han revisado estudios sobre la neurotoxicidad de los tratamientos oncológicos en los que han encontrado que ésta causa cambios estructurales y muestra sus efectos tardíos en blanca que tiene que ver con los déficits atencionales (64,65) .…”

“…Bernabeu et al (2003), han revisado estudios sobre la neurotoxicidad de los tratamientos oncológicos en los que han encontrado que ésta causa cambios estructurales y muestra sus efectos tardíos en blanca que tiene que ver con los déficits atencionales (64,65) . De otro lado, se han estudiado personas tratadas de cáncer de colon y de seno con 5-fluorouracil (5-FU) el que se asocia con daño retardado a la mielina (66) . En uno de estos estudios se encontró que el 61% de mujeres tratadas con este agente presentó un declive en atención, aprendizaje y velocidad de procesamiento que no estaban relacionados a ninguna otra causa ni variable demográfica, y que no mostraron recuperación aún un año después.…”