Dihydropyrimidine Dehydrogenase Activity in Human Peripheral Blood Mononuclear Cells and Liver: Population Characteristics, Newly Identified Deficient Patients, and Clinical Implication in 5-Fluorouracil Chemotherapy

Zhihong Lu, Ruiwen Zhang, Robert B. Diasio

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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, Sj. Soong, and R. B. Diasio. Cancer Res., SO: 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 0360 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.

Original languageEnglish (US)
Pages (from-to)5433-5438
Number of pages6
JournalCancer research
Volume53
Issue number22
StatePublished - Nov 15 1993

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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