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Int. J. Mol. Sci. 2015, 16(4), 8884-8895; doi:10.3390/ijms16048884

Undetected Toxicity Risk in Pharmacogenetic Testing for Dihydropyrimidine Dehydrogenase

1
Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, Milan 20157, Italy
2
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy
3
Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", Faculty of Medicine and Surgery, Second University of Naples, Naples 80138, Italy
4
Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco 23842, Italy
5
Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital "Luigi Sacco", Università di Milano, Milan 20157, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Camile S. Farah
Received: 26 February 2015 / Revised: 30 March 2015 / Accepted: 13 April 2015 / Published: 21 April 2015
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
View Full-Text   |   Download PDF [671 KB, uploaded 21 April 2015]

Abstract

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer. View Full-Text
Keywords: single nucleotide polymorphisms; fluoropyrimidines; dihydropyrimidine dehydrogenase; toxicity; pharmacogenetics single nucleotide polymorphisms; fluoropyrimidines; dihydropyrimidine dehydrogenase; toxicity; pharmacogenetics
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Falvella, F.S.; Caporale, M.; Cheli, S.; Martinetti, A.; Berenato, R.; Maggi, C.; Niger, M.; Ricchini, F.; Bossi, I.; Bartolomeo, M.D.; Sottotetti, E.; Bernardi, F.F.; de Braud, F.; Clementi, E.; Pietrantonio, F. Undetected Toxicity Risk in Pharmacogenetic Testing for Dihydropyrimidine Dehydrogenase. Int. J. Mol. Sci. 2015, 16, 8884-8895.

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