Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy.
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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发表时间：
1993-11
期刊：
影响因子：
11.2
通讯作者：
Zhihong Lu;Ruiwen Zhang;R. Diasio
中科院分区：
文献类型：
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作者：
Zhihong Lu;Ruiwen Zhang;R. Diasio
二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（FUra）催化的起始酶和限速酶。我们实验室以前的研究证明了DPD在癌症患者中的临床重要性（G。D.作者：J-P Heggie，D. S.克罗斯，W。J. Huster和R. B。迪亚西奥癌症研究所，47：2203 - 2206，1987; B. e.哈里斯河，巴西-地Song，S-j. Soong，and R. B。迪亚西奥癌症研究所，50：197 - 201，1990），特别是在患有DPD缺乏症的患者中，其在FUra治疗后经历严重的FUra毒性（包括死亡）[R. B。Diasio，T. L.海狸和J. T。卡彭特J. Clin. Invest.，81：47 - 51，1988; B. e.哈里斯，J.T. Carpenter和R. B。迪亚西奥Cancer（Phila.），68：499 - 501，1991]。我们现在建议，DPD活性的测量可能是有用的，在癌症患者的常规筛查前FURA治疗。在本文中，我们描述了以下一系列的研究：（a）我们开发了一个敏感，准确，和精确的DPD检测和储存方法，以稳定DPD活性，允许大规模的DPD筛查癌症患者;（B）我们证明了正常分布（高斯分布）的人DPD活性从外周血单核细胞（PBM-DPD）在人口研究。新鲜和冷冻样品的PBM-DPD基线分别为0.425 +/-0.124（SD）和0.189 +/-0.064 nmol/min/mg蛋白。新鲜和冷冻样本的95%和99%分布范围也被确定，为DPD缺乏患者的检测提供了标准;（c）我们确定了9名患有严重或部分DPD缺乏的新患者;（d）我们确定了人类肝脏DPD活性的基线，其显示为0.360 +/-0.182 nmol/min/mg蛋白质（冷冻样品）;（e）我们对缺陷患者的肝脏DPD进行了初步评估。两名缺陷患者的肝脏DPD活性低与PBM-DPD活性低相关。利用本实验室制备的抗人肝DPD多克隆抗体（Z.卢河，巴西-地Zhang和R. B。迪亚西奥J. Biol. Chem.，二百六十七：17102 - 17109，1992），蛋白质印迹分析表明，与正常受试者相比，DPD缺陷患者的肝胞质溶胶中DPD蛋白减少。这些结果可能有助于提高FUra化疗的有效性和/或减轻其毒性。
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.