Dihydropyrimidine Dehydrogenase Deficiency and Fluorouracil-Related Toxicity

Br J Cancer. 1999 Feb;79(3-4):627-30. doi: 10.1038/sj.bjc.6690098.

Abstract

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. We report lymphocytic DPD data concerning a group of 53 patients (23 men, 30 women, mean age 58, range 36-73), treated by 5-FU-based chemotherapy in different French institutions and who developed unanticipated 5-FU-related toxicity. Lymphocyte samples (standard collection procedure) were sent to us for DPD determination (biochemical method). Among the whole group of 53 patients, 19 had a significant DPD deficiency (DD; below 150 fmol min(-1) mg(-1) protein, i.e. less than 70% of the mean value observed from previous population study). There was a greater majority of women in the DD group (15 out of 19, 79%) compared with the remaining 34 patients (15 out of 34, 44%, P<0.014). Toxicity was often severe, leading to patient death in two cases (both women). The toxicity score (sum of WHO grading, theoretical range 0-20) was twice as high in patients with marked DD (below 100 pmol min(-1) mg(-1) protein, n = 11, mean score = 13.2) compared with patients with moderate DD (between 150 and 100 pmol min(-1) mg(-1) protein, n = 8, mean score = 6.8), P = 0.008. In the DD group, there was a high frequency of neurotoxic syndromes (7 out of 19, 37%). The two deceased patients both had severe neurotoxicity. The occurrence of cardiac toxicity was relatively rare (1 out of 19, 5%). These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile.

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Digestive System / drug effects
  • Digestive System / pathology
  • Dihydrouracil Dehydrogenase (NADP)
  • Female
  • Fluorouracil / adverse effects*
  • Fluorouracil / metabolism
  • Fluorouracil / pharmacokinetics
  • Humans
  • Lymphocytes / enzymology
  • Male
  • Middle Aged
  • Mucous Membrane / drug effects
  • Mucous Membrane / pathology
  • Neoplasms / drug therapy
  • Neutropenia / chemically induced
  • Oxidoreductases / deficiency*
  • Sex Factors
  • Thrombocytopenia / chemically induced

Substances

  • Antimetabolites, Antineoplastic
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil