Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity.

Abstract

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases and it catalyses the reduction of thymine and uracil to 5,6-dihydrothymine and 5,6-dihydrouracil, respectively. DPD is also responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. 5FU is one of the few drugs that shows some antitumour activity against various otherwise untreatable tumours including carcinomas of the gastrointestinal tract, breast, ovary and skin. Although the cytotoxic effects of 5FU are probably directly mediated by the anabolic pathways, the catabolic route plays a significant role since more than 80% of the administered 5FU is catabolised by DPD. The important role of DPD in the chemotherapy with 5FU has been shown in cancer patients with a complete or near-complete deficiency of this enzyme. These patients suffered from severe (neuro)toxicity including death, following 5FU chemotherapy.1,2 It has been suggested that patients suffering from 5FU toxicities due to a low activity of DPD are genotypically het-erozygous for a mutant allele of the gene encoding DPD.3 Furthermore, the frequency of heterozygotes in the normal population has been estimated to be as high as 3%.3 In this study we investigated the cDNA and a genomic region of the DPD gene of a cancer patient experiencing severe toxicity following 5FU treatment, for the presence of mutations.KeywordsDihydropyrimidine DehydrogenaseGuanidinium ThiocyCatabolic RouteSplice Donor SequenceDihydropyrimidine Dehydrogenase DeficiencyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.