China
Africa
Explore chapters and articles related to this topic
Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are homozygous or heterozygous for these variations may have complete or partial DPD deficiency (an estimated 0.2% of individuals have complete DPD deficiency). Those patients with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines including myelosuppression, neurotoxicity, and hand-foot syndrome.
Dihydropyrimidine Dehydrogenase Deficiency and Fluoropyrimidine-Toxicity
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
André B. P. van Kuilenburga, Eva Gross
To date, numerous decreased function variants have been described in DPYD together with dose recommendations based on the gene activity score [70, 80]. In patients who are heterozygous for a “loss-of-function” (LoF) mutation in DPYD, a dose reduction of 50% has been recommended [70, 80]. Carriers of decreased function variants may tolerate higher doses of fluoropyrimidines when compared to carriers of LoF variants and a dose reduction of 25–50% has been proposed [70, 80]. Pretreatment genotyping for the c.1905+1G>A mutation, followed by dose reduction in carriers has been shown to decrease the percentage of patients experiencing severe toxicity will maintaining 5FU levels similar to that observed in wild-type patients [81]. Until recently, fluoropyrimidine treatment in completely DPD deficient patients has been generally discouraged [70]. Recently, however, it has been demonstrated that patients with a complete DPD deficiency can be successfully treated with extremely low doses of fluoropyrimidines [41].
Precision medicine for colorectal cancer
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Candan Hızel, Şükrü Tüzmen, Arsalan Amirfallah, Gizem Çalıbaşı Koçal, Duygu Abbasoğlu, Haluk Onat, Yeşim Yıldırım, Yasemin Baskın
The DPYD gene contains 23 exons and is located on chromosome 1p22. More than 30 genetic polymorphisms in DPYD caused reduced function or nonfunctional DPD enzyme leading to reduced clearance of 5-FU resulting in increased 5-FU toxicity in CRC patients (Del Re et al., 2010). DPD deficiency occurs in 4%–5% of the population (Deenen et al., 2011b). The most common genetic variant of the DPYD gene with partial or complete DPD deficiency is due to a G to A point mutation within the 5′-splicing site of intron 14 (IVS14 + 1G > A) called DPYD*2A (rs3918290) polymorphism. DPYD*2A leads to catalytically inactive enzyme with a frequency of approximately 1% in Caucasians. DPD activity is reduced by 50% in heterozygous genotype resulting in increased 5-FU exposure. However, DPD activity in patients with homozygous DPYD*2A is about 0% (van Kuilenburg et al., 2001; Meulendijks et al., 2016a, 2016b; Deenen et al., 2016). In patients with complete DPD, nonfloropyrimidin-based treatment is recommended instead of fluoropyrimidines, or if fluoropyrimidines treatment is imperative for attentive monitoring, a starting dose reduction of approximately 10% is recommended (Caudle et al., 2013). However, some variants do not lead to completely inactive enzymes; the variant c. 1129-5923C > G (rs75017182), known as haplotype B3, is a deeply intronic variant encoding partially nonfunctional protein expression with enzyme activity 50% lower in homozygous individuals (Meulendijks et al., 2016a, 2016b).
DPYD and TYMS polymorphisms as predictors of 5 fluorouracil toxicity in colorectal cancer patients
Published in Journal of Chemotherapy, 2023
Yassine Khalij, Imtinen Belaid, Sana Chouchane, Dorra Amor, Asma Omezzine, Nabila Ben rejeb, Slim ben Ahmed, Ali Bouslama
Dihydropyrimidine dehydrogenase (DPD) deficiency is a significant determinant of severe 5-FU-associated toxicity [3]. DPD is the initial and rate-limiting enzyme in the degradation of 5-FU. Because DPD catabolizes more than 80% of the administered 5-FU, patients with a partial or complete DPD deficiency have a strongly reduced capacity to degrade 5-FU and, therefore, an increased likelihood of suffering from severe and sometimes fatal multi-organ toxicity [3, 4]. Many mutations and polymorphisms have been described in the gene (DPYD) encoding DPD, and ample evidence shows that carriers of the variant allele have an increased risk of developing toxicity [5, 6]. In principle, pharmacogenetics-guided dosing will enable the identification of patients at risk of developing severe toxicity before the start of fluoropyrimidine-based chemotherapy [7].
Joint Belgian recommendation on screening for DPD-deficiency in patients treated with 5-FU, capecitabine (and tegafur)
Published in Acta Clinica Belgica, 2022
Veerle Casneuf, Ivan Borbath, Marc Van den Eynde, Yolanda Verheezen, Wim Demey, Alain G Verstraete, Kathleen Bm Claes, Vincent Haufroid, Karen P Geboes
It is recommended to test for DPD deficiency before starting 5FU-based chemotherapy. In order not to delay treatment, oncologists should implement phenotype and/or targeted genotype testing early in the management of malignancies requiring fluoropyrimidines. In order not to lose time through shipment, it is necessary to send blood samples directly to the labs performing the tests. Both phenotyping and targeted genotyping test can be performed simultaneously, or a stepwise procedure can be implemented, first performing phenotyping because of its higher sensitivity followed by genotyping for uracilemia above the threshold of 14 ng/mL. However, in order not to lose time with this stepwise procedure, the flow of samples has to be secured, e.g. by already taking two blood samples before initiation of 5-FU and sending the second sample to the genetic laboratory immediately when a high uracil (or a low UH2/U ratio) is detected. If we calculate 17 000 new tests per year in Belgium, the cost for screening all patients would amount up to 2.5 million euro for targeted genotyping. The cost of performing screening with phenotyping alone would be up to 680 000 euro.If we would use a stepwise approach, estimating that up to 15% of patients would have an elevated uracil and require genetic testing, the cost would be around 1 million euro.
Capecitabine in treating patients with advanced, persistent, or recurrent cervical cancer: an active and safe option?
Published in Expert Opinion on Drug Safety, 2021
Federica Tomao, Giuseppe Caruso, Lucia Musacchio, Violante Di Donato, Maria Cristina Petrella, Monica Verrico, Silverio Tomao, Pierluigi Benedetti Panici, Ludovico Muzii, Innocenza Palaia
Capecitabine is an oral pro-drug that is enzymatically metabolized by thymidine phosphorylase (TP) to cytotoxic 5-fluorouracil (5-FU). The latter inhibits thymidylate synthase (TS) and thus the synthesis of thymidine monophosphate (dTMP), the active form of thymidine required for DNA de novo synthesis [30]. The dihydropyrimidine dehydrogenase (DPD) is another enzyme involved in the 5-FU metabolic pathway, which catabolizes 5-FU to inactive dihydrofluorouracil in the liver, resulting in increased urinary excretion (Figure 1) [31]. Basically, the TP/DPD ratio biologically determines the intracellular 5-FU concentration [32]. Extensive studies have associated both profound and partial DPD deficiency (3–5% of the general population) with severe, unanticipated toxicities after 5-FU administration, including mucositis, hair loss, diarrhea, neutropenia, skin rash, and neurologic toxicities [33]. Research on the molecular basis behind DPD deficiency has highlighted various sequence variants of the DPYD gene, hence screening patients for DPD deficiency prior to 5 FU or capecitabine administration should be recommended [34].