title: Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene.
abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU), and it is suggested that patients 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 toxicity, an analysis of the DPD activity, the DPD gene, and the clinical presentation of patients suffering from severe toxicity after the administration of 5FU was performed. Our study demonstrated that in 59% of the cases, a decreased DPD activity could be detected in peripheral blood mononuclear cells. It was observed that 55% of patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of patients with a normal DPD activity (P = 0.01). Furthermore, the onset of toxicity occurred, on average, twice as fast in patients with low DPD activity as compared with patients 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 activity 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; 43%). Two novel missense mutations 496A-->G (M166V) and 2846A-->T (D949V) were detected in exon 6 and exon 22, respectively. Our results demonstrated that at least 57% (8 of 14) of the patients with a reduced DPD activity have a molecular basis for their deficient phenotype.
authors.affiliation: Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, The Netherlands. a.b.vankuilenburg@amc.uva.nl
authors.forename: A B
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: J
authors.initials: J
authors.lastname: Haasjes
authors.forename: D J
authors.initials: DJ
authors.lastname: Richel
authors.forename: L
authors.initials: L
authors.lastname: Zoetekouw
authors.forename: H
authors.initials: H
authors.lastname: Van Lenthe
authors.forename: R A
authors.initials: RA
authors.lastname: De Abreu
authors.forename: J G
authors.initials: JG
authors.lastname: Maring
authors.forename: P
authors.initials: P
authors.lastname: Vreken
authors.forename: A H
authors.initials: AH
authors.lastname: van Gennip
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use* / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP); D005091:Exons; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use* / Q000633:toxicity*; D005838:Genotype; D006098:Granulocytes / Q000201:enzymology; D006801:Humans; D007438:Introns; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil