Van Kuilenburg André B P, Meinsma Rutger, Zoetekouw Lida, Van Gennip Albert H
Emma Children's Hospital and Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, the Netherlands.
Int J Cancer. 2002 Sep 20;101(3):253-8. doi: 10.1002/ijc.10599.
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity. We evaluated the importance of DPD deficiency, gender and the presence of the IVS14+1G>A mutation in the etiology of 5-FU toxicity. In 61% of cases, decreased DPD activity could be detected in peripheral blood mononuclear cells. Furthermore, the number of females (65%) in the total group of patients appeared to be higher than the number of males (35%) (p = 0.03). Patients with partial DPD deficiency appeared to have a 3.4-fold higher risk of developing grade IV neutropenia than patients with normal DPD activity. Analysis of the DPYD gene of patients suffering from grade IV neutropenia for the presence of the IVS14+1G>A mutation showed that 50% of the patients investigated were heterozygous or homozygous for the IVS14+1G>A mutation. Adopting a threshold level for DPD activity of 70% of that observed in the normal population, 14% of the population is prone to the development of severe 5-FU-associated toxicity. Below this threshold level, 90% of individuals heterozygous for a mutation in the DPYD gene can be identified. Considering the common use of 5-FU in the treatment of cancer, the severe 5-FU-related toxicities in patients with low DPD activity and the apparently high prevalence of the IVS14+1G>A mutation, screening of patients at risk before administration of 5-FU is warranted.
二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5-FU）分解代谢的起始和限速酶，有人认为该酶部分缺乏的患者有发生严重5-FU相关毒性的风险。我们评估了DPD缺乏、性别以及IVS14+1G>A突变在5-FU毒性病因中的重要性。在61%的病例中，可在外周血单个核细胞中检测到DPD活性降低。此外，患者总数中的女性数量（65%）似乎高于男性数量（35%）（p = 0.03）。与DPD活性正常的患者相比，部分DPD缺乏的患者发生IV级中性粒细胞减少的风险似乎高3.4倍。对发生IV级中性粒细胞减少的患者的DPYD基因进行IVS14+1G>A突变分析，结果显示，在接受调查的患者中有50%为IVS14+1G>A突变的杂合子或纯合子。采用正常人群中观察到的DPD活性的70%作为阈值水平，14%的人群易于发生严重的5-FU相关毒性。低于该阈值水平时，可识别出90%的DPYD基因突变杂合个体。鉴于5-FU在癌症治疗中的广泛应用、低DPD活性患者中严重的5-FU相关毒性以及IVS14+1G>A突变明显较高的患病率，在给予5-FU之前对有风险的患者进行筛查是必要的。
