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Dihydropyrimidine dehydrogenase activity and the IVS14+1G>A mutation in patients developing 5FU‐related toxicity
Author(s) -
Magné Nicolas,
EtienneGrimaldi MarieChristine,
Cals Laurent,
Renée Nicole,
Formento JeanLouis,
Francoual Mireille,
Milano Gérard
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02869.x
Subject(s) - medicine , toxicity , dihydropyrimidine dehydrogenase , population , gastroenterology , chemotherapy , fluorouracil , thymidylate synthase , environmental health
What is already known about this subject • Dihydropyrimidine dehydrogenase (DPD) deficiency is known to be a major cause of severe 5FU‐related toxicity. • A link has been previously shown between 5FU toxicity and either low enzyme activity measured in peripheral blood mononuclear cells (PMNC) or germinal DPD mutations. • The link between the most common DPD mutation (IVS14+1G>A) and PMNC enzyme activity is poorly documented. What this study adds • This paper provides the largest series of case‐reports ( n = 131) with 5FU‐related toxicity, analyzed for both PMNC‐DPD activity and the IVS14+1G>A mutation. • A very low incidence of the IVS14+1G>A mutation (2.2%) was observed in this selected Caucasian population. • Present data suggest that IVS14+1 mutation screening has limited effectiveness in identifying patients at risk for severe 5FU toxicity. Also, patients with normal PMNC‐DPD activity may develop life‐threatening toxicity. Aims To examine retrospectively the relationship between DPD phenotype/genotype and the intensity of 5FU toxicity. Methods One hundred and thirty‐one case‐reports (81 women, 50 men) with 5FU‐related toxicity were analyzed. Results The lower the DPD activity (10–504 pmol min −1 mg −1 ), the higher the toxicity grade was scored ( P < 0.01). Toxicity‐related deaths occurred in nine patients (eight women) who significantly expressed lower DPD activity than other patients. Two of the deceased patients had normal DPD activity. The IVS14+1G>A mutation, analyzed in 93 patients, was detected in two patients (nonlethal toxicity). Conclusions The IVS14+1G>A mutation may not help prevent toxicity and patients with normal DPD activity may develop life‐threatening 5FU toxicity.