EXPERIMENTAL NEUROTOXICITY OF 5-FLUOROURACIL AND ITS DERIVATIVES IS DUE TO POISONING BY THE MONOFLUORINATED ORGANIC METABOLITES, MONOFLUOROACETIC ACID AND ALPHA-FLUORO-BETA-ALANINE

被引:78
作者
OKEDA, R
SHIBUTANI, M
MATSUO, T
KUROIWA, T
SHIMOKAWA, R
TAJIMA, T
机构
[1] Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, No. 5-45, Tokyo, 113, Yushima 1-chome, Bunkyo-ku
关键词
α-Fluoro-β-alanine; 5-Fluorouracil; Monofluoroacetic acid; Neurotoxicity; Vacuolation;
D O I
10.1007/BF00662639
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Two metabolites of 5-fluorouracil (FU), monofluoroacetic acid (FA) and α-fluoro-β-alanine (FBAL), were continuously administered into the left ventricle of the brain in cats for up to 1 month to investigate the mechanissm of neurotoxicity of FU and its derivatives. The cumulative doses of FU and FBAL over a 1-month period were 1.5-45 mg (20 cats) and 0.2-4.8 mg (21 cats), respectively. As controls for each experimental group, acetic acid (AA) and β-alanine (BAL) were administered. In terms of survival time in relation to the cumulative dose and molecular weight, FBAL was more toxic than FA. Neuropathologically, two types of change, vacuoles and necrosis/softening-like change, were found. The vacuoles were 20-50 μm in diameter, and distributed mainly in the cerebellar nuclei, white matter and the tectum and tegmentum of the brain stem in both experimental groups. Electron microscopically, these vacuoles were due to splitting of the myelin intraperiod line or separation between the axon and the innermost layer of myelin. Necrosis/softening-like change occurred preferentially in the FBAL group and was located symmetrically in the superior and inferior colliculi, oculomotor nuclei and thalamus. Both types of neuropathological change, especially those in the FBAL group, were similar to those found in cats orally administered with FU and its derivatives. It was, therefore, concluded that the subacute and chronic neurotoxicity of FU and its derivatives in dogs and cats is due to intoxication with the monofluorinated organic metabolites, FA and FBAL, and that the direct action of FA and FBAL on myelin and the action of FBAL on energy metabolism or vessels of the mid brain were proposed as the main pathogenetic factor involved. © 1990 Springer-Verlag.
引用
收藏
页码:66 / 73
页数:8
相关论文
共 13 条
[1]   THE NEUROPATHOLOGY OF VIGABATRIN [J].
BUTLER, WH .
EPILEPSIA, 1989, 30 :S15-S17
[2]  
CHENOWETH MB, 1949, PHARMACOL REV, V1, P383
[3]   NEUROPATHOLOGY OF VIGABATRIN [J].
GRAHAM, D .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1989, 27 :S43-S45
[4]  
GRIFFIN JW, 1979, NEUROTOXICOLOGY, V1, P299
[5]  
JASPER HH, 1954, STEREOTAXIC ATLAS DI, P14
[6]  
JUBB K V, 1956, J Comp Pathol, V66, P217, DOI 10.1016/S0368-1742(56)80023-4
[7]   SUBACUTE LEUKOENCEPHALOPATHY INDUCED BY CARMOFUR, A 5-FLUOROURACIL DERIVATIVE [J].
KUZUHARA, S ;
OHKOSHI, N ;
KANEMARU, K ;
HASHIMOTO, H ;
NAKANISHI, T ;
TOYOKURA, Y .
JOURNAL OF NEUROLOGY, 1987, 234 (06) :365-370
[8]  
OKEDA R, 1988, ACTA PATHOL JAPON, V38, P1255
[9]   NEUROPATHOLOGIC STUDY ON CHRONIC NEUROTOXICITY OF 5-FLUOROURACIL AND ITS MASKED COMPOUNDS IN DOGS [J].
OKEDA, R ;
KARAKAMA, T ;
KIMURA, S ;
TOIZUMI, S ;
MITSUSHIMA, T ;
YOKOYAMA, Y .
ACTA NEUROPATHOLOGICA, 1984, 63 (04) :334-343
[10]  
PATTISON FLM, 1966, HDB EXPT PHARMACOLOG, V20, P387