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Upfront DPD Deficiency Detection to Secure 5-FU Administration: Part 1 – Where Do We Stand?

[ Vol. 4 , Issue. 2 ]

Author(s):

Manon Launay, Joseph Ciccolini*, Anne Rodallec, Claire Fournel, Florence Duffaud, Sebastien Salas and Bruno Lacarelle   Pages 74 - 81 ( 8 )

Abstract:


Background: 5-Fluoro-Uracil (5-FU) ranks among the most widely prescribed anticancer agents worldwide. Fluoropyrimidines are a mainstay in the treatment of numerous solid tumors, mostly used in combination with other cytotoxics, targeted therapies or biologics. Because most of the administered 5-FU dose will undergo extensive catabolism driven by dihydropyrimidine dehydrogenase (DPD), a liver enzyme that converts 5-FU into inactive metabolite, drug dosing is particularly high in some settings such as digestive or head-and-neck cancers. Variations in fluoropyrimidine disposition are a major cause for the erratic pharmacokinetics profile observed in cancer patients. Because of the elevated doses administered, DPD-deficient patients are likely to experience lifethreatening toxicities and those are now a rising issue regarding pre-emptive strategies to be undertaken to improve safety. Numerous clinical reports and meta-analysis have investigated on possible strategies to forecast DPD deficiency, thus opening the way to preventive adaptive dosing strategies with 5-FU or oral capecitabine.

Objective: This Part-1 aims at covering the achievements, limits and perspectives of current strategies to detect DPD deficiency at the bedside.

Method: A Pubmed research was performed regarding genotyping and phenotyping DPD deficiency, as well as their cost-effectiveness studies, in order to discuss and compare their performance.

Results and Conclusion: To date, defining the best upfront method to sort patients on their DPD status remains a challenging issue because genotyping approaches show a low sensitivity with respect to the actual number of 5-FU-related toxicity reported cases, and that phenotyping approaches have several technical limitations.

Keywords:

5-FluoroUracil, fluoropyrimidine, dihydropyrimidine dehydrogenase, personalized medicine, DPD deficiency, pharmacogenetics, toxicity.

Affiliation:

Laboratoire de Pharmacocinetique Clinique, La Timone University hospital of Marseille, APHM Marseille, Laboratoire de Pharmacocinetique Clinique, La Timone University hospital of Marseille, APHM Marseille, SMARTc Unit, Inserm S_911 CRO2, Aix Marseille University, Marseille, Medical Oncology Unit, La Timone University Hospital of Marseille, APHM Marseille, Medical Oncology Unit, La Timone University Hospital of Marseille, APHM Marseille, Medical Oncology Unit, La Timone University Hospital of Marseille, APHM Marseille, Laboratoire de Pharmacocinetique Clinique, La Timone University hospital of Marseille, APHM Marseille

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