Dihydropyrimidine dehydrogenase deficiency in an Indian population.

Yale University School of Medicine, New Haven, CT 06520, USA.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.57). 10/2006; 58(3):396-401. DOI: 10.1007/s00280-005-0174-5
Source: PubMed

ABSTRACT Dihydropyrimidine dehydrogenase (DPD) deficiency is prevalent in 3-5% of the Caucasian population; however, the frequency of this pharmacogenetic syndrome in the Indian population and other racial and ethnic groups remains to be elucidated.
We describe an Indian patient who presented to clinic for the treatment of gastric adenocarcinoma with 5-flurouracil (5-FU) therapy who subsequently was diagnosed with DPD deficiency by using the peripheral blood mononuclear cell (PBMC) DPD radioassay. This observation prompted us to examine the data generated from healthy (cancer-free) Indian subjects who were enrolled in a large population study to determine the sensitivity and specificity of the uracil breath test (UraBT) in the detection of DPD deficiency. Thirteen Indian subjects performed the UraBT. UraBT results were confirmed by PBMC DPD radioassay.
The Indian cancer patient demonstrated reduced DPD activity (0.11 nmol/min/mg protein) and severe 5-FU toxicities commonly associated with DPD deficiency. Of the 13 Indian subjects [ten men and three women; mean age, 26 years (range: 21-31 years)] enrolled in the UraBT, 12 Indian subjects demonstrated UraBT breath profiles and PBMC DPD activity within the normal range; one Indian subject demonstrated a reduced breath profile and partial DPD deficiency.
DPD deficiency is a pharmacogenetic syndrome which is also present in the Indian population. If undiagnosed, the DPD deficiency can lead to death. Future epidemiological studies would be helpful to determine the prevalence of DPD deficiency among racial and ethnic groups, allowing for the optimization of 5-FU chemotherapy.

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    ABSTRACT: Fluoropyrimidines (e.g., 5-FU, oral capecitabine) remain unchallenged as reference drugs for treating numerous solid tumors in adults, including digestive, head and neck, and breast cancers. The wide inter-patient variability observed in the pharmacokinetic profiles of these drugs is mainly caused by the erratic activity of dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for fluoropyrimidines catabolism. Beside circadian variations, DPD activity can be affected as well by DPYD gene polymorphisms, and genetic and epigenetic regulations, both in the liver and at the tumor site, which can have a strong impact on drug-induced toxicities and/or treatment outcome. In this respect, studying the causes of DPD deficiency allows for better understanding of the pharmacodynamics of 5-FU and capecitabine. Consequently, several strategies have been proposed to predict and anticipate the impact of variations in DPD on the clinical outcome of cancer patients receiving fluoropyrimidine chemotherapy.
    Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response part II in serie: Cancer Drug Discovery and Development TM, Edited by Federico Innocenti, 01/2009: chapter Dihydropyrimidine Dehydrogenase (Dpyd) Gene Polymorphism: Portrait of a Serial Killer: pages 249-265; Humana Press., ISBN: 978-1-60327-088-5
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    ABSTRACT: Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumors and remain the backbone of many combination regimens. Despite their clinical benefit, fluoropyrimidines are associated with gastrointestinal and hematologic toxicities, which often lead to treatment discontinuation. 5-FU undergoes complex metabolism, dihydropyrimidine dehydrogenase (DPD) being the rate-limiting enzyme of inactivation of 5-FU and its prodrugs. Several studies have demonstrated significant associations between severe toxicities by fluoropyrimidines and germline polymorphisms of DPD gene. To date, more than 30 SNPs and deletions have been identified within DPD, the majority of these variants having no functional consequences on enzymatic activity. However, the identification of deficient DPD genotypes may help identify poor-metabolizer patients at risk of developing potentially life-threatening toxicities after standard doses of fluoropyrimidines.
    09/2010; 1(3):495-502. DOI:10.1007/s13167-010-0041-2
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    ABSTRACT: Background: Dihydropyrimidine dehydrogenase (DPD) encoded by DPYD gene is the major enzyme involved in metabolism of 5-flurouracil (5-FU), a pyrimidine analogue used in cancer chemotherapy. Although very effective as a cancer therapeutic drug, if not rapidly metabolized, 5-FU may prove lethal. Single nucleotide variants (SNVs) within DPYD that modulate DPD enzyme activity contribute to 5-FU toxicity. Study: This study looked for DPYD SNVs common in the Indian population that might be associated with variable DPD activity and drug toxicity. To achieve this, sequencing analysis was performed of all 23 exons and flanking intronic regions of the DPYD gene in a cohort of 50 healthy adult Indians. This study detected 22 SNVs including intronic, synonymous and non-synonymous changes in the DPYD gene, of which six have not been documented before. Allelic frequency was calculated for the observed variants and linkage disequilibrium (LD) analysis was performed on variants with frequency ≥0.1 to identify haplotypes. Conclusions: This study provides a brief overview of the genetic polymorphism in DPYD in Indians and emphasizes the need for a large scale extensive study to establish markers associated with the frequently observed variable drug metabolism.
    Annals of Human Biology 08/2014; 42(1). DOI:10.3109/03014460.2014.942365 · 1.15 Impact Factor


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May 30, 2014