| 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. | |
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MedLine Citation:
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PMID: 12209976 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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André B P Van Kuilenburg; Rutger Meinsma; Lida Zoetekouw; Albert H Van Gennip |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 101 ISSN: 0020-7136 ISO Abbreviation: Int. J. Cancer Publication Date: 2002 Sep |
Date Detail:
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Created Date: 2002-09-04 Completed Date: 2002-09-26 Revised Date: 2007-07-24 |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 253-8 Citation Subset: IM |
Copyright Information:
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Copyright 2002 Wiley-Liss, Inc. |
Affiliation:
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Emma Children's Hospital and Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, the Netherlands. a.b.vanKuilenburg@amc.uva.nl |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Antimetabolites, Antineoplastic / adverse effects* Dihydrouracil Dehydrogenase (NADP) Exons / genetics Female Fluorouracil / adverse effects* Gene Frequency Genotype Granulocytes / enzymology Humans Leukocytes, Mononuclear / enzymology Male Middle Aged Mutation / genetics* Neoplasm Staging Neoplasms / drug therapy, enzymology*, genetics Neutropenia / chemically induced* Oxidoreductases / deficiency*, genetics* Polymorphism, Restriction Fragment Length RNA Splice Sites / genetics* Risk Factors |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites, Antineoplastic; 0/RNA Splice Sites; 51-21-8/Fluorouracil; EC 1.-/Oxidoreductases; EC 1.3.1.2/Dihydrouracil Dehydrogenase (NADP) |
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