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

Han R, Yang YM, Dietrich J, Luebke A, Mayer-Pröschel M, Noble M - J. Biol. (2008)

Bottom Line: Despite their clinical importance, almost nothing is known about the basis for such effects.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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

ABSTRACT

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.

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Cell-type analyses of BrdU+ cells in control and 5-FU-treated animals at early and late time points after completion of treatment. Co-analysis of BrdU incorporation with antigen expression was conducted as described in Materials and methods. Both control and 5-FU-treated groups were analyzed at (a,b) day 1 and (c,d) day 56 to evaluate the immediate and long-term effects of 5-FU treatment. Results indicate that division of both DCX+ neuronal progenitors and Olig2+oligodendrocyte precursors was reduced by systemic exposure to 5-FU. In the CC, the reduction in apparent division of Olig2+ cells was proportionate to the overall reduction in all BrdU+ cells. In the SVZ, there was an enhanced reduction of DCX+ cells from among the BrdU+population at day 1 but not at day 56. In the DG, there was an enhanced reduction in the dividing DCX+ population at both day 1 and day 56. In addition, the proportion of GFAP+ cells in the CC was increased among the BrdU+ population at both time points examined. Data are mean ± s.e.m; *p < 0.05, in comparisons with control animals (confidence interval = 95%, by unpaired, two-tailed Student's t-test).
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Figure 5: Cell-type analyses of BrdU+ cells in control and 5-FU-treated animals at early and late time points after completion of treatment. Co-analysis of BrdU incorporation with antigen expression was conducted as described in Materials and methods. Both control and 5-FU-treated groups were analyzed at (a,b) day 1 and (c,d) day 56 to evaluate the immediate and long-term effects of 5-FU treatment. Results indicate that division of both DCX+ neuronal progenitors and Olig2+oligodendrocyte precursors was reduced by systemic exposure to 5-FU. In the CC, the reduction in apparent division of Olig2+ cells was proportionate to the overall reduction in all BrdU+ cells. In the SVZ, there was an enhanced reduction of DCX+ cells from among the BrdU+population at day 1 but not at day 56. In the DG, there was an enhanced reduction in the dividing DCX+ population at both day 1 and day 56. In addition, the proportion of GFAP+ cells in the CC was increased among the BrdU+ population at both time points examined. Data are mean ± s.e.m; *p < 0.05, in comparisons with control animals (confidence interval = 95%, by unpaired, two-tailed Student's t-test).

Mentions: We found that neuronal precursors and oligodendrocyte precursors were both affected in vivo. In the CC, where there was a 42.6 ± 2.7% reduction in the number of BrdU+ cells in tissue sections from animals sacrificed 1 day after the completion of treatment (Figure 4b), the proportion of BrdU+ cells that were Olig2+ was similar between controls and treated animals (Figure 5a,b). This result also held true at day 56, when the proportion of Olig2+ cells among the BrdU+population was unchanged in untreated and treated animals, despite a continued 53.2 ± 12.4% reduction in the total number of BrdU+cells observed (Figure 5c,d). As >90% of the BrdU+ cells in the CC were Olig2+, these results indicate that the reduction in DNA synthesis observed in this tissue predominantly affected O-2A/OPCs [97,98,101].


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

Han R, Yang YM, Dietrich J, Luebke A, Mayer-Pröschel M, Noble M - J. Biol. (2008)

Cell-type analyses of BrdU+ cells in control and 5-FU-treated animals at early and late time points after completion of treatment. Co-analysis of BrdU incorporation with antigen expression was conducted as described in Materials and methods. Both control and 5-FU-treated groups were analyzed at (a,b) day 1 and (c,d) day 56 to evaluate the immediate and long-term effects of 5-FU treatment. Results indicate that division of both DCX+ neuronal progenitors and Olig2+oligodendrocyte precursors was reduced by systemic exposure to 5-FU. In the CC, the reduction in apparent division of Olig2+ cells was proportionate to the overall reduction in all BrdU+ cells. In the SVZ, there was an enhanced reduction of DCX+ cells from among the BrdU+population at day 1 but not at day 56. In the DG, there was an enhanced reduction in the dividing DCX+ population at both day 1 and day 56. In addition, the proportion of GFAP+ cells in the CC was increased among the BrdU+ population at both time points examined. Data are mean ± s.e.m; *p < 0.05, in comparisons with control animals (confidence interval = 95%, by unpaired, two-tailed Student's t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2397490&req=5

Figure 5: Cell-type analyses of BrdU+ cells in control and 5-FU-treated animals at early and late time points after completion of treatment. Co-analysis of BrdU incorporation with antigen expression was conducted as described in Materials and methods. Both control and 5-FU-treated groups were analyzed at (a,b) day 1 and (c,d) day 56 to evaluate the immediate and long-term effects of 5-FU treatment. Results indicate that division of both DCX+ neuronal progenitors and Olig2+oligodendrocyte precursors was reduced by systemic exposure to 5-FU. In the CC, the reduction in apparent division of Olig2+ cells was proportionate to the overall reduction in all BrdU+ cells. In the SVZ, there was an enhanced reduction of DCX+ cells from among the BrdU+population at day 1 but not at day 56. In the DG, there was an enhanced reduction in the dividing DCX+ population at both day 1 and day 56. In addition, the proportion of GFAP+ cells in the CC was increased among the BrdU+ population at both time points examined. Data are mean ± s.e.m; *p < 0.05, in comparisons with control animals (confidence interval = 95%, by unpaired, two-tailed Student's t-test).
Mentions: We found that neuronal precursors and oligodendrocyte precursors were both affected in vivo. In the CC, where there was a 42.6 ± 2.7% reduction in the number of BrdU+ cells in tissue sections from animals sacrificed 1 day after the completion of treatment (Figure 4b), the proportion of BrdU+ cells that were Olig2+ was similar between controls and treated animals (Figure 5a,b). This result also held true at day 56, when the proportion of Olig2+ cells among the BrdU+population was unchanged in untreated and treated animals, despite a continued 53.2 ± 12.4% reduction in the total number of BrdU+cells observed (Figure 5c,d). As >90% of the BrdU+ cells in the CC were Olig2+, these results indicate that the reduction in DNA synthesis observed in this tissue predominantly affected O-2A/OPCs [97,98,101].

Bottom Line: Despite their clinical importance, almost nothing is known about the basis for such effects.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus