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Development, validation, and use of ...

Mattison, Lori K.

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Development, validation, and use of a novel [2-carbon-13] uracil breath test to detect dihydropyrimidine dehydrogenase deficiency.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Development, validation, and use of a novel [2-carbon-13] uracil breath test to detect dihydropyrimidine dehydrogenase deficiency./
Author:	Mattison, Lori K.
Description:	179 p.
Notes:	Adviser: Robert B. Diasio.
Contained By:	Dissertation Abstracts International67-07B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3226748
ISBN:	9780542801297

Development, validation, and use of a novel [2-carbon-13] uracil breath test to detect dihydropyrimidine dehydrogenase deficiency.
Mattison, Lori K.

Development, validation, and use of a novel [2-carbon-13] uracil breath test to detect dihydropyrimidine dehydrogenase deficiency. - 179 p.

Adviser: Robert B. Diasio.

Thesis (Ph.D.)--The University of Alabama at Birmingham, 2006.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal codominantly inherited pharmacogenetic syndrome associated with severe, unanticipated, 5-fluorouracil (5-FU) toxicity in cancer patients. As the initial and rate-limiting enzyme of the pyrimidine catabolic pathway, DPD degrades more than 80% of an administered dose of 5-FU. When DPD deficient cancer patients are administered 5-FU, dangerously increased 5-FU AUC, exposure, and toxicity may occur. DPD deficiency is present in 3-5% of the general population.

ISBN: 9780542801297Subjects--Topical Terms:

1017730
Biology, Genetics.

Development, validation, and use of a novel [2-carbon-13] uracil breath test to detect dihydropyrimidine dehydrogenase deficiency.
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020 $a 9780542801297
035 $a (UMI)AAI3226748
035 $a AAI3226748
040 $a UMI $c UMI
100 1 $a Mattison, Lori K. $3 1281951
245 1 0 $a Development, validation, and use of a novel [2-carbon-13] uracil breath test to detect dihydropyrimidine dehydrogenase deficiency.
300 $a 179 p.
500 $a Adviser: Robert B. Diasio.
500 $a Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3728.
502 $a Thesis (Ph.D.)--The University of Alabama at Birmingham, 2006.
520 $a Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal codominantly inherited pharmacogenetic syndrome associated with severe, unanticipated, 5-fluorouracil (5-FU) toxicity in cancer patients. As the initial and rate-limiting enzyme of the pyrimidine catabolic pathway, DPD degrades more than 80% of an administered dose of 5-FU. When DPD deficient cancer patients are administered 5-FU, dangerously increased 5-FU AUC, exposure, and toxicity may occur. DPD deficiency is present in 3-5% of the general population.
520 $a Given the frequency of DPD deficiency and the severity of DPD-mediated 5-FU toxicity, development of a diagnostic test to rapidly screen cancer patients for DPD deficiency prior to 5-FU administration is critical. Unfortunately, due to a lack of characterization of the majority of the 30 reported DPYD (gene that encodes DPD) sequence variations, development of a clinically useful genotypic test is not feasible. Therefore the development of a rapid phenotypic test, an oral [2-13C] uracil breath test (UraBT), was the primary objective of this dissertation research. The major findings of this research are the following: (1) the amino acid sequence of the DPD enzyme is conserved among mammals and invertebrates, suggesting that a comparative genetic approach may be used to prioritize DPYD sequence variations for future functional characterization; (2) DPD deficient individuals may be identified by reduced breath 13CO 2 concentrations and altered breath 13CO2 kinetics following oral administration of [2-13C] uracil in UraBT; (3) UraBT sensitivity and specificity is 100 and 96%; (4) DPD deficient subjects have altered plasma [2-13C] uracil and [2- 13C] dihydrouracil pharmacokinetics; (5) PBMC DPD activity, [2- 13C] uracil and [2-13C] dihydrouracil pharmacokinetics significantly correlate with the UraBT DOB50; (6) the UraBT is a rapid assay which may be used to screen previously unexamined populations, such as Indians, for DPD deficiency; and (7) the African American population, particularly African American women, have may have significantly reduced pyrimidine catabolism as demonstrated by reduced UraBT DOB50 values and PBMC DPD activity, which may increase the risk of 5-FU toxicity. These data support the future evaluation and use of the UraBT as a screening assay to identify DPD deficiency in cancer patients prior to 5-FU administration.
590 $a School code: 0005.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Engineering, Biomedical. $3 1017684
650 4 $a Health Sciences, Pharmacology. $3 1017717
650 4 $a Health Sciences, Toxicology. $3 1017752
690 $a 0369
690 $a 0383
690 $a 0419
690 $a 0541
710 2 0 $a The University of Alabama at Birmingham. $3 1019443
773 0 $t Dissertation Abstracts International $g 67-07B.
790 $a 0005
790 1 0 $a Diasio, Robert B., $e advisor
791 $a Ph.D.
792 $a 2006
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3226748