Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: Identification of new mutations in the DPD gene

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzy me in the catabolism of 5-fluorouracil (5FU), and it is suggested that pati ents with a partial deficiency of this enzyme are at risk for developing a severe 5FU-associated toxicity, To evaluate the importance of this specific type of inborn error of pyrimidine metabolism in the etiology of 5FU toxic ity, an analysis of the DPD activity, the DPD gene, and the clinical presen tation of patients suffering from severe toxicity after the administration of 5FU was performed. Our study demonstrated that in 59% of the cases, a de creased DPD activity could he detected in peripheral blood mononuclear cell s. It was observed that 55% of patients with a decreased DPD activity suffe red from grade IV neutropenia compared with 13% of patients with a normal D PD activity (P = 0.01). Furthermore, the onset of toxicity occurred, on ave rage, twice as fast in patients with low DPD activity as compared with pati ents with a normal DPD activity (10.0 +/- 7.6 versus 19.1 +/- 15.3 days; P < 0.05). Analysis of the DPD gene of 14 patients with a reduced DPD activit y revealed the presence of mutations in 11 of 14 patients, with the splice site mutation IVS14+1G-->A being the most abundant one (6 of 14 patients; 4 3%). Two novel missense mutations 496A-->G (M166V) and 2846A-->T (D949V) we re detected in exon 6 and exon 22, respectively. Our results demonstrated t hat at least 57% (8 of 14) of the patients with a reduced DPD activity have a molecular basis for their deficient phenotype.