title: Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation.
abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity. We evaluated the importance of DPD deficiency, gender and the presence of the IVS14+1G>A mutation in the etiology of 5-FU toxicity. In 61% of cases, decreased DPD activity could be detected in peripheral blood mononuclear cells. Furthermore, the number of females (65%) in the total group of patients appeared to be higher than the number of males (35%) (p = 0.03). Patients with partial DPD deficiency appeared to have a 3.4-fold higher risk of developing grade IV neutropenia than patients with normal DPD activity. Analysis of the DPYD gene of patients suffering from grade IV neutropenia for the presence of the IVS14+1G>A mutation showed that 50% of the patients investigated were heterozygous or homozygous for the IVS14+1G>A mutation. Adopting a threshold level for DPD activity of 70% of that observed in the normal population, 14% of the population is prone to the development of severe 5-FU-associated toxicity. Below this threshold level, 90% of individuals heterozygous for a mutation in the DPYD gene can be identified. Considering the common use of 5-FU in the treatment of cancer, the severe 5-FU-related toxicities in patients with low DPD activity and the apparently high prevalence of the IVS14+1G>A mutation, screening of patients at risk before administration of 5-FU is warranted.
authors.affiliation: Emma Children's Hospital and Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, the Netherlands. a.b.vanKuilenburg@amc.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: Van Kuilenburg
authors.forename: Rutger
authors.initials: R
authors.lastname: Meinsma
authors.forename: Lida
authors.initials: L
authors.lastname: Zoetekouw
authors.forename: Albert H
authors.initials: AH
authors.lastname: Van Gennip
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D042943:Dihydrouracil Dehydrogenase (NADP); D005091:Exons / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D005787:Gene Frequency; D005838:Genotype; D006098:Granulocytes / Q000201:enzymology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D009503:Neutropenia / Q000139:chemically induced*; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D022821:RNA Splice Sites / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D022821:RNA Splice Sites; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil