Neuropathologic study on chronic neurotoxicity of 5-fluorouracil and its masked compounds in dogs

Abstract

5-Fluorouracil (FU) and its masked compounds tegafur (FT) and carmofur (HCFU) were administered orally to Beagle dogs daily for 6 months, and their chronic neurotoxic effects were examined morphologically. In ten dogs that survived the 6-month treatment large vacuoles produced by splitting of the intraperiod line of myelin were observed in the fornix in the wall of the third ventricle. In severely affected dogs large vacuoles developed in the medial preoptic area, medial portion of the internal capsule, the area around the subthalamic nucleus and the mammillo-thalamic tract. Axons of myelinated fibers affected by vacuolation were generally well maintained, and destruction of myelin was not detected. Though proliferation of glia cells or abnormality of oligodendroglia was not detected, a lipid deposit covered by a single layer membrane was observed in the cell bodies and processes of astrocytes. No abnormality was detected by electron microscopy in the cerebrum, inferior colliculus, cerebellum, or pons. Of eight dogs that died during the treatment period, large vacuoles were observed in the fornix in the wall of the third ventricle of four dogs treated for more than 1 month, and large vacuoles were present in the inferior colliculus in two dogs of the FT group in the above four dogs. In the HCFU group, the interruption of treatment for 6 months resulted in alleviation or disappearance of the vacuolar lesions. The above findings suggest that the neurotoxicity of FU and its masked compounds FT and HCFU in long-term treatment produces changes morphologically identical with one another in respect to the site of their manifestation and nature of lesion, that their common degraded product alpha-fluoro-beta-alanine (FBAL) plays a crucial role in their neurotoxic actions, and that vacuolar lesions, to which myelin was more vulnerable than neurons, can develop where the toxic substance readily deposits and accumulates.

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

“…The present results therefore support the earlier report of Davis et al (1994). These authors demonstrated that GW776 protected dogs from the neurotoxicity induced by a 26-h continuous infusion of 5-FU at three doses (1.6, 4 or 16 mg kg-' 24 h-') and suggested with others (Koenig and Patel, 1970;Okeda et al, 1984Okeda et al, , 1990) that 5-FU catabolites are responsible for this dose-limiting toxicity in dogs and cats, which are particularly sensitive.…”

“…GW776 greatly improved the anti-tumour efficacy, the oral bioavailability and the therapeutic index of 5-FU in animals (Baccanari et al, 1993;Cao et al, 1994). Moreover, Davis et al (1994) demonstrated that GW776 protected dogs from 5-FU-induced neurotoxicity that could be due to FAC (Koenig and Patel, 1970;Okeda et al, 1984Okeda et al, , 1990.…”

Effects of selected repeated intravitreal chemotherapeutic agents

“…Vacuolization of myelinated central nervous system tissues have been reported with its use (16). Topical 5-FU has been found to cause conjunctivitis, blepharitis, circumorbital edema, ocular pain, and corneal ulceration (11,22).…”

Diffusion-weighted MR imaging of Carmofur-induced leukoencephalopathy

“…Okeda et al [8,9] investigated carmofur-induced encephalopathy neuropathologically in dogs and cats, and found intramyelinic edema, including vacuole formation. Vacuoles measured 20±50 mm in diameter and were produced by splitting of the intraperiod line of myelin and necrosis without myelin destruction.…”