Lu Z, Zhang R, Carpenter J T, Diasio R B
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.
Clin Cancer Res. 1998 Feb;4(2):325-9.
Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), one of the most widely used chemotherapeutic agents in the treatment of breast cancer. The objective of this study was to determine the population characteristics of DPD activity in patients with breast cancer as well as the frequency of DPD deficiency in this population. DPD activity in peripheral blood mononuclear cells (PBM-DPD) was determined in 360 patients with breast cancer, with the mean PBM-DPD (0.26 +/- 0.01 nmol/min/mg protein) being significantly lower than that observed in female controls (0.44 +/- 0.02 nmol/min/mg protein; P < 0.01). ANOVA analysis examining the significance of differences in DPD activity among various groups indicated that only disease difference (breast cancer versus normal subjects) was significant after adjustments for race and age. In the present study, 21 (5.8%) patients were considered to be DPD deficient, indicating that this pharmacogenetic syndrome may be more common than anticipated (no DPD-deficient individual was found in the controls). Significantly lower DPD activity in patients with breast cancer may predispose to 5-FU-associated toxicity. These results provide further rationale for individualizing the 5-FU dose, thus reducing the risk of toxicity and/or improving therapeutic efficacy in patients with breast cancer.
二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5-FU）分解代谢过程中的首个限速酶，5-氟尿嘧啶是治疗乳腺癌时最广泛使用的化疗药物之一。本研究的目的是确定乳腺癌患者中DPD活性的人群特征以及该人群中DPD缺乏症的发生率。测定了360例乳腺癌患者外周血单核细胞中的DPD活性（PBM-DPD），其平均PBM-DPD（0.26±0.01纳摩尔/分钟/毫克蛋白质）显著低于女性对照组（0.44±0.02纳摩尔/分钟/毫克蛋白质；P<0.01）。方差分析检测不同组间DPD活性差异的显著性，结果表明在对种族和年龄进行校正后，只有疾病差异（乳腺癌患者与正常受试者）具有显著性。在本研究中，21例（5.8%）患者被认为存在DPD缺乏，这表明这种药物遗传学综合征可能比预期更为常见（对照组中未发现DPD缺乏个体）。乳腺癌患者中显著较低的DPD活性可能会导致与5-FU相关的毒性。这些结果为5-FU剂量个体化提供了进一步的理论依据，从而降低乳腺癌患者的毒性风险和/或提高治疗效果。
