Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene

Abstract

Objectives: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrmidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. Design and Methods:Restriction fragment length polymorphism (RFLP) and DNA sequence analysis were performed on genomic DNA and mRNA.Results: In 400 patients that were diagnosed with cancer and were eligible for 5-FU treatment, 14 patients were found to be heterozygous for the splice-site mutation DPYD IVS14+1G>A, which corresponds to a population frequency of 3.5%. Two novel variants in the DPYD gene were identified. The first case was heterozygous for DPYD c.1796T>C (p.M599T). In the second case, we observed heterozygosity for the splice-site mutation DPYD IVS14+17A>G. Conclusions:We report two new DPYD gene variants, of which DPYD c.1796T>C is potentially pathogenic, whereas DPYD IVS14+17A>G is suggested as a variant without clinical significance.

Assessment of sequential combination of 5-fluorouracil-loaded-chitosan-nanoparticles and ALA-photodynamic therapy on HeLa cell line

“…Therefore, the use of CNPs used as immunological adjuvants to induce both humoral and cell-mediated immunity could be promising. , is a first -line anticancer drug, which efficacy is affected by its low lipophilicity and low bioavailability and its several side effects [8].…”

In Vitro and In Vivo Evaluation of a Folate-Targeted Copolymeric Submicrohydrogel Based on N-Isopropylacrylamide as 5-Fluorouracil Delivery System

“…5-Fluorouracil (5-FU) is one of the chemotherapeutic compounds most used for the treatment of a great variety of tumors [1], such as colorectal cancer [2][3][4], breast cancer [5], pancreatic cancer [6], or gastric cancer [7]. It is an antimetabolite of pyrimidine analogue type that acts mainly through the inhibition of synthesis of DNA and RNA during the S-phase of the cell cycle.…”

“…This enzyme is present in most of the tissues including liver and peripheral blood mononuclear cells, although the DPD activity is much greather in liver than in any other tissue as gastrointestinal tract, kidney and spleen [40]. DPD activity is highly variable in the population [1]. In this way, a considerable variability (interpatient and intrapatient) in pharmacokinetic studies of both bolus and continuous infusion therapy of 5-FU is thought to be due mainly to variability in DPD activity and consequent variability in the rate of catabolism.…”

“…More than 85% of an administered dose of this anticancer agent is degraded through the catabolic pathway in the liver by dihydropyrimidine dehydrogenase (DPD) [1,41], and only a reduced part of 5-FU is available for bioactivation. DPD is the rate-controlling enzyme of endogenous pyrimidine and fluoropyrimidine catabolism [1].…”

“…More than 85% of an administered dose of this anticancer agent is degraded through the catabolic pathway in the liver by dihydropyrimidine dehydrogenase (DPD) [1,41], and only a reduced part of 5-FU is available for bioactivation. DPD is the rate-controlling enzyme of endogenous pyrimidine and fluoropyrimidine catabolism [1]. This enzyme is present in most of the tissues including liver and peripheral blood mononuclear cells, although the DPD activity is much greather in liver than in any other tissue as gastrointestinal tract, kidney and spleen [40].…”