Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity

• Published in: British journal of cancer Vol. 79; no. 3-4; pp. 627 - 630
• Main Authors: MILANO, G, ETIENNE, M. C, PIERREFITE, V, BARBERI-HEYOB, M, DEPORTE-FETY, R, RENEE, N
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.02.1999
• Subjects: Adult; Aged; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Digestive System - drug effects; Digestive System - pathology; Dihydrouracil Dehydrogenase (NADP); Drug toxicity and drugs side effects treatment; Female; Fluorouracil - adverse effects; Fluorouracil - metabolism; Fluorouracil - pharmacokinetics; Humans; Lymphocytes - enzymology; Male; Medical sciences; Middle Aged; Miscellaneous (drug allergy, mutagens, teratogens...); Mucous Membrane - drug effects; Mucous Membrane - pathology; Neoplasms - drug therapy; Neutropenia - chemically induced; Oxidoreductases - deficiency; Pharmacology. Drug treatments; Regular; Sex Factors; Thrombocytopenia - chemically induced; Antineoplastic agent; Human; Enzyme; Toxicity; Deficiency; Fluoropyrimidine derivatives; Clinical form; Dehydrogenase; Epidemiology; Chemotherapy; Enzymatic activity; Pyrimidine derivatives; Catabolism; Dihydropyridine derivatives; Oxidoreductases; Fluorouracil
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6690098

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.