TY - JOUR
T1 - Dihydropyrimidine Dehydrogenase Activity in Human Peripheral Blood Mononuclear Cells and Liver
T2 - Population Characteristics, Newly Identified Deficient Patients, and Clinical Implication in 5-Fluorouracil Chemotherapy
AU - Lu, Zhihong
AU - Zhang, Ruiwen
AU - Diasio, Robert B.
PY - 1993/11/15
Y1 - 1993/11/15
N2 - 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.
AB - 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.
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M3 - Article
C2 - 8221682
AN - SCOPUS:0027426408
SN - 0008-5472
VL - 53
SP - 5433
EP - 5438
JO - Cancer research
JF - Cancer research
IS - 22
ER -