Increased risk of grade IV neutropenia after administration of 5‐fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: High prevalence of the IVS14+1g>a mutation
Reads0
Chats0
TLDR
Screening of patients at risk before administration of 5‐FU‐related toxicities in patients with low DPD activity and the apparently high prevalence of the IVS14+1G>A mutation is warranted.Abstract:
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity. We evaluated the importance of DPD deficiency, gender and the presence of the IVS14+1G>A mutation in the etiology of 5-FU toxicity. In 61% of cases, decreased DPD activity could be detected in peripheral blood mononuclear cells. Furthermore, the number of females (65%) in the total group of patients appeared to be higher than the number of males (35%) (p = 0.03). Patients with partial DPD deficiency appeared to have a 3.4-fold higher risk of developing grade IV neutropenia than patients with normal DPD activity. Analysis of the DPYD gene of patients suffering from grade IV neutropenia for the presence of the IVS14+1G>A mutation showed that 50% of the patients investigated were heterozygous or homozygous for the IVS14+1G>A mutation. Adopting a threshold level for DPD activity of 70% of that observed in the normal population, 14% of the population is prone to the development of severe 5-FU-associated toxicity. Below this threshold level, 90% of individuals heterozygous for a mutation in the DPYD gene can be identified. Considering the common use of 5-FU in the treatment of cancer, the severe 5-FU-related toxicities in patients with low DPD activity and the apparently high prevalence of the IVS14+1G>A mutation, screening of patients at risk before administration of 5-FU is warranted.read more
Citations
More filters
Journal ArticleDOI
A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip
TL;DR: Combination of a mathematical modeling approach (PK-PD modeling) and an in vitro experimental approach (microCCA) provides a novel platform with improved predictability for testing drug toxicity and can help researchers gain a better insight into the drug's mechanism of action.
Journal ArticleDOI
Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice
Sharon J. Gardiner,Evan J. Begg +1 more
TL;DR: The current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes is summarized and no other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation.
Journal ArticleDOI
Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil.
TL;DR: A deficiency of DPD appears to be an important pharmacogenetic syndrome, and patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia.
Journal ArticleDOI
Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group
M. Schwab,Ulrich M. Zanger,Claudia Marx,Elke Schaeffeler,Kathrin Klein,Jürgen Dippon,Reinhold Kerb,Julia Blievernicht,Joachim Fischer,Ute Hofmann,Carsten Bokemeyer,Michel Eichelbaum +11 more
TL;DR: DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients, and toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.
Journal ArticleDOI
Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing.
Kelly E. Caudle,Caroline F. Thorn,Teri E. Klein,Jesse J. Swen,Howard L. McLeod,Robert B. Diasio,Matthias Schwab +6 more
TL;DR: Evidence from the published literature supporting this association and dosing recommendations for fluoropyrimidines based on DPYD genotype are summarized and provided.
References
More filters
PatentDOI
Measurement of protein using bicinchoninic acid
TL;DR: This new method maintains the high sensitivity and low protein-to-protein variation associated with the Lowry technique and demonstrates a greater tolerance of the bicinchoninate reagent toward such commonly encountered interferences as nonionic detergents and simple buffer salts.
Journal ArticleDOI
Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.
Pascal Piedbois,Ph. Rougier,Marc Buyse,J.P. Pignon,Louise Ryan,R Hansen,Benny Zee,B Weinerman,J Pater,Cynthia G. Leichman,John S. Macdonald,Jacqueline Benedetti,J Lokich,J Fryer,G Brufman,R Isacson,Agnès Laplanche,E Levy +17 more
TL;DR: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival, and the hematologic toxicity is much less important in patients who receive 5-fu CI, but hand-foot syndrome is frequent in this group of patients.
Journal Article
Colorectal Tumors Responding to 5-Fluorouracil Have Low Gene Expression Levels of Dihydropyrimidine Dehydrogenase, Thymidylate Synthase, and Thymidine Phosphorylase
Dennis Salonga,Kathleen D. Danenberg,Martin R. Johnson,Ralf Metzger,Susan Groshen,Denice D. Tsao-Wei,Heinz-Josef Lenz,C. Gail Leichman,L Leichman,Robert B. Diasio,Peter V. Danenberg +10 more
TL;DR: The results of this study show that intratumoral gene expression level of DPD is associated with tumor response to 5-FU and that the use of more than one independent determinant of response permits the identification of a high percentage of responding patients.
Journal ArticleDOI
Multicenter Phase II Study of Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer
Joanne L. Blum,Stephen E. Jones,Aman U. Buzdar,Patricia Mucci LoRusso,Irene Kuter,Charles E. Vogel,Bruno Osterwalder,Hans Ulrich Burger,Cheryl Stoner Brown,Tom Griffin +9 more
TL;DR: Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic metastatic breast cancer and has a favorable toxicity profile with the added advantage of being an oral drug administered at home.
Journal Article
Clinical Pharmacokinetics of 5-Fluorouracil and Its Metabolites in Plasma, Urine, and Bile
TL;DR: This study provides the first comprehensive analysis of the formation and excretion of F Ura metabolites in plasma, urine, and bile following i.v. bolus administration of FUra in humans.