caa a22 4500 46576858X CHVBK 20180323111922.0 cr unu---uuuuu 170327e19900101xx s 000 0 eng 10.1007/BF00662639 doi (NATIONALLICENCE)springer-10.1007/BF00662639 Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and α-fluoroβ-alanine [Elektronische Daten] [R. Okeda, M. Shibutani, T. Matsuo, T. Kuroiwa, R. Shimokawa, T. Tajima] Summary: 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. Springer-Verlag, 1990 5-Fluorouracil nationallicence Monofluoroacetic acid nationallicence α-Fluoro-β-alanine nationallicence Neurotoxicity nationallicence Vacuolation nationallicence Okeda R. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut Shibutani M. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut Matsuo T. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut Kuroiwa T. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut Shimokawa R. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut Tajima T. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut Acta Neuropathologica Springer-Verlag 81/1(1990-01-01), 66-73 0001-6322 81:1<66 1990 81 401 https://doi.org/10.1007/BF00662639 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00662639 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Okeda R. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Shibutani M. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Matsuo T. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Kuroiwa T. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Shimokawa R. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Tajima T. Department of Neuropathology, Medical Research Institute, Tokyo Medical & Dental University, No. 5-45, Yushima 1-chome, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 773 0- Acta Neuropathologica Springer-Verlag 81/1(1990-01-01), 66-73 0001-6322 81:1<66 1990 81 401 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer