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Medline ® Abstract for Reference 71

of 'Enterotoxicity of chemotherapeutic agents'

71
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Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients.
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Del Re M, Michelucci A, Di Leo A, Cantore M, Bordonaro R, Simi P, Danesi R
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EPMA J. 2015;6(1):17. Epub 2015 Sep 2.
 
BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when administered standard doses of 5-FU and its prodrugs.
MATERIALS AND METHODS: We selected three patients with colorectal adenocarcinoma who displayed unexpected severe adverse reactions after treatment with 5-FU and capecitabine. To investigate the possible involvement of deficient variants of the DPD gene (DPYD), a denaturing HPLC (dHPLC) approach followed by target exon sequencing of DPYD was performed on DNA extracted from peripheral blood.
RESULTS: Three novel non-synonymous mutations of DPYD, c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants of DPYD and the compatibility of adverse reactions with fluoropyrimidine treatment, the novel variants were associated with a poor-metabolizer phenotype.
CONCLUSIONS: Stratification of patients on the basis of their genotype may help prevent toxicity, and the large body of evidence about the pathogenesis of fluoropyrimidine-induced adverse reactions strongly encourages the adoption of best practice recommendations to appropriately address this important clinical issue. This approach is of utmost importance within a preventive, prognostic, and personalized approach to patient care in the oncology setting.
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Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, 55, Via Roma, 56126 Pisa, Italy.
PMID