| DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS. | |
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MedLine Citation:
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PMID: 18846242 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVES: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. METHODOLOGY: Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-(13)C uracil breath test (UraBT). RESULTS: Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2', 3', 5'-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients of 112.8; PDR of 49.4%) and borderline normal values revealed 1 to be DPD-deficient (DOB(50) of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among (DOB(50) DPD-deficient patients (28%). CONCLUSIONS: DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique. |
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Authors:
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M Wasif Saif; Kostas Syrigos; Ranee Mehra; Lori K Mattison; Robert B Diasio |
Publication Detail:
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Type: JOURNAL ARTICLE |
Journal Detail:
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Title: Pakistan journal of medical sciences quarterly Volume: 23 ISSN: 1681-715X ISO Abbreviation: Pak J Med Sci Q Publication Date: 2007 |
Date Detail:
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Created Date: 2009-3-5 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100913117 Medline TA: Pak J Med Sci Q Country: - |
Other Details:
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Languages: ENG Pagination: 832-839 Citation Subset: - |
Affiliation:
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Yale University School of Medicine, New Haven, CT Athens Medical School, Sotiria General Hospital, Athens, Greece. |
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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R01 CA062164-06//NCI NIH HHS |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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