Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity.

Severe neurotoxicity due to 5-fluorouracil (FUra) has previously been described in a patient with familial pyrimidinemia. We now report the biochemical basis for both the pyrimidinemia and neurotoxicity in a patient we have recently studied. After administration of a "test" dose of FUra (25 mg/m2, 600 microCi[6-3H]FUra by intravenous bolus) to a patient who had previously developed neurotoxicity after FUra, a markedly prolonged elimination half-life (159 min) was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FUra. Using a sensitive assay for dihydropyrimidine dehydrogenase in peripheral blood mononuclear cells, we demonstrated complete deficiency of enzyme activity in the patient and partial deficiency of enzyme activity in her father and children consistent with an autosomal recessive pattern of inheritance. Patients who are deficient in this enzyme are likely to develop severe toxicity after FUra administration.

Effect of prenatal ionizing radiation on the visual cortex and hippocampus of newborn squirrel monkeys.

Five squirrel monkeys were exposed to 200 rads whole-body ionizing irradiation (60Co) at 0.4 rads per second on approximately the seventy-fifth day of gestation, and six squirrel monkeys were sham-irradiated. The mean cortical depth and the mean number of neurons per mm3 in the visual cortex was less in irradiated animals than in controls, but the differences were not statistically significant. The mean number of glial cells in this cortical region was significantly lower in the irradiated animals. An analysis of variance of the combined spine count data from apical, basal, and oblique dendrites revealed a significantly lower number of dendritic spines on basal dendrites in irradiated than in control animals in Meynert neurons in the visual cortex of irradiated offspring. In the hippocampus, the depth of the stratum oriens and the combined depth of the strata radiatum, lacunosum, and moleculare were significantly less in irradiated than in control animals, although the difference in the depth of the pyramidal layer, considered individually, was not statistically significant. The mediolateral width of the CA-1, CA-2, and CA-3 zones, as seen in transverse section, was significantly less in irradiated animals than in controls. The number of dendritic spines per unit length of pyramidal cell dendrite in the CA-1 zone and the total number of pyramidal neurons in the CA-1, Ca-2 and CA-3 zones, per transverse section, were significantly lower in irradiated than in control brains. Canonical correlations provided statistical evidence for greater radiation vulnerability of the hippocampus compared to motor and visual areas of the cerebral cortex.