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Dihydropyrimidine Dehydrogenase Activity in Human Peripheral Blood Mononuclear Cells and Liver: Population Characteristics, Newly Identified Deficient Patients, and Clinical Implication in 5-Fluorouracil Chemotherapy
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TLDR
A sensitive, accurate, and precise DPD assay and a storage method to stabilize DPD activity are developed, permitting large scale DPD screening in cancer patients and a normal distribution (Gaussian distribution) of human D PD activity from peripheral blood mononuclear cells (PBM-DPD) in a population study.Abstract:
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (FUra), one of the most widely used anticancer drugs. Previous studies from our laboratory demonstrated the clinical importance of DPD in cancer patients (G. D. Heggie, J-P. Sommadossi, D. S. Cross, W. J. Huster, and R. B. Diasio. Cancer Res., 47: 2203-2206, 1987; B. E. Harris, R. Song, S-j. Soong, and R. B. Diasio. Cancer Res., 50: 197-201, 1990), particularly in those with DPD deficiency who experience severe FUra toxicity (including death) following FUra treatment [R. B. Diasio, T. L. Beavers, and J. T. Carpenter. J. Clin. Invest., 81: 47-51, 1988; B. E. Harris, J. T. Carpenter, and R. B. Diasio. Cancer (Phila.), 68: 499-501, 1991]. We now suggest that measurement of DPD activity may be useful in routine screening of cancer patients prior to FUra treatment. In this paper, we describe the following serial studies: (a) we developed a sensitive, accurate, and precise DPD assay and a storage method to stabilize DPD activity, permitting large scale DPD screening in cancer patients; (b) we demonstrated a normal distribution (Gaussian distribution) of human DPD activity from peripheral blood mononuclear cells (PBM-DPD) in a population study. Baselines for PBM-DPD with fresh and frozen samples were 0.425 +/- 0.124 (SD) and 0.189 +/- 0.064 nmol/min/mg protein, respectively. The 95% and 99% distribution ranges for both fresh and frozen samples were also determined, providing criteria for detection of DPD-deficient patients; (c) we identified nine new patients with profound or partial DPD deficiency; (d) we determined a baseline for human liver DPD activity, which was shown to be 0.360 +/- 0.182 nmol/min/mg protein (frozen samples); (e) we did a preliminary evaluation of liver DPD from deficient patients. Low liver DPD activity in two deficient patients correlated with low PBM-DPD activity. Using a polyclonal antibody raised against human liver DPD in our laboratory (Z. Lu, R. Zhang, and R. B. Diasio. J. Biol. Chem., 267: 17102-17109, 1992), Western blot analysis demonstrated decreased DPD protein in the liver cytosol from DPD-deficient patients compared to normal subjects. These results may be useful in improving the effectiveness and/or lessening the toxicity of FUra chemotherapy.read more
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Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice
Sharon J. Gardiner,Evan J. Begg +1 more
TL;DR: The current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes is summarized and no other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation.
Journal ArticleDOI
Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil.
TL;DR: A deficiency of DPD appears to be an important pharmacogenetic syndrome, and patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia.
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Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group
M. Schwab,Ulrich M. Zanger,Claudia Marx,Elke Schaeffeler,Kathrin Klein,Jürgen Dippon,Reinhold Kerb,Julia Blievernicht,Joachim Fischer,Ute Hofmann,Carsten Bokemeyer,Michel Eichelbaum +11 more
TL;DR: DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients, and toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.
Journal ArticleDOI
Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.
Xiaoxiong Wei,Howard L. McLeod,Julieann McMurrough,Frank J. Gonzalez,Pedro M. Fernández-Salguero +4 more
TL;DR: A genotyping test for the G to A splicing point mutation could be useful in predicting cancer patients prone to toxicity upon administration of potentially toxic 5-FU and for genetic screening of heterozygous carriers and homozygous deficient subjects.
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5-Fluorouracil: Forty-Plus and Still Ticking. A Review of its Preclinical and Clinical Development
TL;DR: The preelinical and clinical pharmacology of 5-FU is reviewed to provide a basis for exploring the novel approachesto permit oral administration of5-FU or its prodrugs that will be described in other articles in this issue.
References
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A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
TL;DR: This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr with little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose.
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Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications.
TL;DR: A method has been devised for the electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets that results in quantitative transfer of ribosomal proteins from gels containing urea.
Journal ArticleDOI
Clinical pharmacology of 5-fluorouracil.
Robert B. Diasio,Barry E. Harris +1 more
TL;DR: 5-Fluorouracil, first introduced as a rationally synthesised anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin.
Journal Article
Clinical Pharmacokinetics of 5-Fluorouracil and Its Metabolites in Plasma, Urine, and Bile
TL;DR: This study provides the first comprehensive analysis of the formation and excretion of F Ura metabolites in plasma, urine, and bile following i.v. bolus administration of FUra in humans.
Journal ArticleDOI
Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity.
TL;DR: A markedly prolonged elimination half-life was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FURA.