Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase

Abstract

Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.

Elevated Risk of Fluoropyrimidine-Associated Toxicity in European Patients with DPYD Genetic Polymorphism: A Systematic Review and Meta-Analysis

“…About 1% to 3% of the fluoropyrimidine metabolite is cytotoxic; fluorodeoxyuridine monophosphate forms a ternary complex with thymidylate synthase and 5,10-methylene tetrahydrofolate, resulting in the inhibition of DNA synthesis. DPD is known to convert approximately 80% to 85% of fluoropyrimidine into inactive dihydrofluorouracil (DHFU) through hepatic metabolism [14]; this is the rate-limiting step in fluoropyrimidine metabolism. DHFU is then converted to fluoro-β-ureidopropionate by dihydropyrimidinease and further changed to fluoro-β-alanine by β-ureidopropionase [15,16].…”

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

“…Following intravenous injection, only 1–5% of prodrug 5-FU is metabolized into active cytotoxic metabolites with approximately 20% being subjected to urinal excretion while the remaining 80% is rapidly degraded in the liver [ 14 ]. Degradation of 5-FU is facilitated by the enzyme dihydropyrimidine dehydrogenase (DPD) that catabolizes the conversion of 5-FU into 5,6-dihydro-5-fluorouracil (DHFU) as the inactive metabolite [ 15 ].…”