Neurotoxic Effects of .Alpha.-Fluoro-.Beta.-Alanine (Fbal) and Fluoroacetic Acid (Fa) on Dogs

Abstract

In order to clarify the mechanism of the neurotoxicity of 5-FU and/or its masked compounds, we studied the effects of alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA) on the formation of vacuolar changes in the dog cerebrum, using the dosage of 3.0 mg/kg/day of FBAL-HCl (FBAL x HCl) and 0.03 mg/kg/day of FA-Na (FA x Na), respectively. These 2 compounds were selected because they are the metabolites of 5-FU claimed to be responsible for the neurotoxic effects of 5-FU and/or its masked compounds, and we wanted to confirm their effects. Tegafur-uracil mixture (UFT) was used as a positive control drug for the formation of vacuolar changes in the dog cerebrum. All compounds were orally administered daily for 3 months to beagle dogs. Each study group consisted of 3 males. Neurotoxic signs such as hyperesthesia and/or excitement, as well as convulsions, were observed in both FBAL x HCl and FA x Na groups; these toxic signs were also found in the UFT group. Slight loss of body weight gain and of food consumption was observed in the FBAL x HCl and UFT groups. Neuropathologically, vacuolar changes were detected in several areas of the dog cerebrum following administration of FBAL x HCl, FA x Na or UFT. In terms of morphology, the neuropathological effects of these 2 drugs were very similar to those induced by UFT. In conclusion, we clearly showed that FBAL is one of the main substances that cause neurotoxic signs and neuropathological changes in dogs intoxicated by 5-FU or its masked compounds. Moreover, FA might be considered to be a causative factor in addition to FBAL.

Successful treatment of a dog with massive 5‐fluorouracil toxicosis

“…14 Studies in dogs examining the mechanism leading to neurotoxicity associated with 5-FU suggest that this medication may lower brain GABA concentration secondary to inhibition of the citric acid cycle by fluorocitrate. 13 Because benzodiazepines potentiate the action of GABA, this may explain why most case reports describing management of 5-FU toxicosis in dogs suggest that seizures are often refractory to standard therapy. 8,9 Levetiracetam, in contrast, acts by binding the synaptic vesicle 2a protein on the presynaptic terminal, thereby limiting synaptic vesicle fusion and neurotransmitter release; the drug does not facilitate the action of GABA.…”

“…11,12 More recent studies in dogs have implicated the metabolites fluoroacetate and ␣-fluoro-␤-alanine as causative agents for the observed neurotoxicosis. 13 Several retrospective case series in the veterinary literature describe the outcomes associated with 5-FU toxicosis in dogs. One case series reported that 5 of 13 dogs treated with 5-FU intravenously at a dose of 10 mg/kg for various neoplasms developed neurotoxicosis; all but one of those affected dogs died.…”

Toxicology of fluoroacetate: a review, with possible directions for therapy research

“…It was also found that a series of other compounds metabolize to FA as intermediate products: these are the anticancer drugs 5-fluorouracil and fluoroethyl nitrosourea, N-(2-fluoroethyl) derivatives of the narcotic analgesics normeperidin and normetazocin, the industrial chemicals fluoroethanol and 1-(di)halo-2-fluoroethanes (Yamashita et al, 2004;Arellano et al, 1998;Yeh and Cheng, 1994;Reifenrath et al, 1980;Tisdale and Brennan, 1985;Tecle and Casida, 1989;Keller et al, 1996;Feldwick et al, 1998). Finally, industrial 'achievements' have led to the appearance of FA in fog and rain (Rompp et al, 2001).…”

New Perspectives in the Treatment of Advanced Gastric Cancer: S-1 as a Novel Oral 5-FU Therapy in Combination with Cisplatin

“…Animal studies in cats showed two types of neuropathological changes induced by FBAL: vacuoles and necrosis/softening-like changes similar to those found in patients following orally administered 5-FU [29]. These neurotoxic effects of FBAL and fluoroacetic acid, another metabolite of 5-FU degradation, were also confirmed in dogs [30]. …”