title: High prevalence of the IVS14 + 1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity.
abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU) and a DPD deficiency is increasingly being recognized as an important pharmacogenetic factor in the aetiology of severe 5FU-associated toxicity. In this study, we evaluated the DPD activity and the prevalence of the common splice site mutation IVS14 + 1G>A in tumour patients suffering from severe grade 3-4 toxicity after the administration of 5FU. DPD activity was measured with a radiochemical assay and screening for the presence of the IVS14 + 1G>A mutation was performed by restriction fragment length polymorphism. A decreased DPD activity could be detected in peripheral blood mononuclear cells in 60% of the cases. Furthermore, a high prevalence of the IVS14 + 1G>A mutation was noted as 28% of all patients were heterozygous or homozygous for this mutation. In patients with a low DPD activity, 42% were heterozygous and one patient (3%) was homozygous for the IVS14 + 1G>A mutation. In contrast, the IVS14 + 1G>A mutation could be detected in only one out of 24 (4%) patients with a normal DPD activity. Our study demonstrates that a DPD deficiency is the major determinant of 5FU-associated toxicity. The apparently high prevalence of the IVS14 + 1G>A mutation warrants genetic screening for this mutation in cancer patients before the administration of 5FU.
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use / Q000633:toxicity*; D006580:Genetic Carrier Screening; D006098:Granulocytes / Q000187:drug effects / Q000201:enzymology; D006720:Homozygote; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D010088:Oxidoreductases / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D000964:Antimetabolites, Antineoplastic; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil