GENETIC POLYMORPHISM OF DIHYDROPYRIMIDINE DEHYDROGENASE

Project: Research project

Description

The long term objective of this project is to improve 5-fluorouracil (5-
FU) chemotherapy in cancer patients by better understanding the recently
reported genetic polymorphism of the pyrimidine catabolic enzyme,
dihydropyrimidine dehyrogenase (also known as dihydrouracil
dehydrogenase, dihydrothymine dehydrogenase, DPD, EC 1.3.1.2) and its
role in determining 5-FU toxicity in patients. Studies in our laboratory
have demonstrated the critical role that DPD has in regulating 5-FU
catabolism and hence 5-FU available for anabolism. Since 5-FU anabolism
determines toxicity, it is hypothesized that decreased DPD activity would
increase 5-FU toxicity. In preliminary studies, several patients with
severe 5-FU toxicity were identified who were profoundly deficient in DPD
activity compared to controls. Family studies demonstrated that DPD
activity is inherited as an autosomal recessive. Subsequent studies of
patients with moderate toxicity revealed DPD activity in an intermediate
range similar to the levels detected in the children or parents
(heterozygotes) in the family studies of the profound deficient patients.
We propose the following: Spec. Aim 1) Determine population distribution
of DPD activity and frequency of genetic deficiency of DPD in the cancer
and non-cancer patient population; Spec. Aim 2) Determine in a
prospective study the relationship between DPD activity and 5-FU
toxicity; Spec Aim 3) Determine biochemical properties of DPD from
peripheral blood mononuclear cells of normal and deficient individuals.
Comparison of DPD from deficient patients with DPD from normal
individuals should provide insight into the mechanism of genetic
polymorphism of DPD. Theses studies should be useful in the future in
predicting which patients may be susceptible to severe 5-FU toxicity,
permitting modification of drug dose before chemotherapy.
StatusFinished
Effective start/end date12/9/9311/30/06

Funding

  • National Institutes of Health: $301,981.00
  • National Institutes of Health: $287,359.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $280,606.00
  • National Institutes of Health: $287,359.00
  • National Institutes of Health: $287,359.00
  • National Institutes of Health
  • National Institutes of Health: $309,233.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $287,359.00

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Dihydrouracil Dehydrogenase (NADP)
Genetic Polymorphisms
Fluorouracil
Dihydropyrimidine Dehydrogenase Deficiency
Gene Expression
Enzymes
Routine Diagnostic Tests
Transcriptional Regulatory Elements
Proteasome Endopeptidase Complex
Ubiquitin
dihydropyrimidinase
Proteins
Organized Financing
Orotate Phosphoribosyltransferase
Uridine Phosphorylase
Uridine Kinase
Mutation
Phosphorylase Kinase
Thymidine Phosphorylase

ASJC

  • Medicine(all)