5-fluorouracil-induced oligodendrocyte death and inhibitory effect of cycloheximide, trolox, and Z-VAD-FMK in murine cortical culture
✍ Scribed by Ki-Hyun Cho; Sung-Min Choi; Byeong-Chae Kim; Seung-Han Lee; Man-Seok Park; Myeong-Kyu Kim; Jong-Keun Kim
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 322 KB
- Volume
- 100
- Category
- Article
- ISSN
- 0008-543X
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✦ Synopsis
Abstract
BACKGROUND
5‐fluorouracil (5‐FU) is a widely used anticancer drug. One of the adverse effects of this drug is selective cerebral white matter injury, but to the authors' knowledge its mechanism has not been well documented. The current study was performed to investigate the mechanism of cerebral white matter injury caused by 5‐FU and to develop the intervention to attenuate its injury in vitro.
METHODS
Mixed oligodendrocyte/astrocyte cells were dissociated from specimens taken from approximately 2‐day‐old postnatal mouse cortex and cultured for 3–4 weeks. The culture cells were exposed to 5‐FU, cycloheximide, emetine, Z‐VAD‐fmk, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo(F)‐quinoxaline (NBQX), Trolox, and epigallocatechin gallate. Oligodendrocyte cell death was assessed by counting the number of viable galactocerebroside‐positive cells per × 100 field.
RESULTS
Mixed oligodendrocyte/astrocyte culture cells that were exposed to 5‐FU (at doses of 10 μM, 30 μM, and 100 μM) for 24 hours ensued concentration‐dependent oligodendrocyte death. The majority of oligodendrocytes, but few astrocytes, were injured by 100 μM 5‐FU. Trolox, a vitamin E analog antioxidant, as well as cycloheximide (a protein synthesis inhibitor) and Z‐VAD‐fmk (a caspase inhibitor), significantly attenuated the 5‐FU–induced oligodendrocyte death. However, NBQX, an alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, did not appear to effect the 5‐FU–induced oligodentrocyte death.
CONCLUSIONS
The findings of the current study suggested that 5‐FU led to oligodendrocyte death rather than astrocyte death by way of the apoptotic process, whereas antioxidants may prevent the 5‐FU–induced oligodendrocyte cell death in vitro. Cancer 2004;100:1484–90. © 2004 American Cancer Society.