Etienne M C, Milano G, Renée N, Lagrange J L, Dassonville O, Thyss A, Schneider M, François E, Fleming R, Demard F
Centre Antoine-Lacassagne, Nice, France.
Bull Cancer. 1995 Sep;82(9):705-10.
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme of 5-fluorouracil (5-FU) catabolism. The clinical importance of DPD has recently been demonstrated with the identification of severe and/or lethal 5-FU-related toxicity in patients with suspected or proven DPD deficiency revealed in lymphocytes. We conducted a prospective study on 185 cancer patients in order to evaluate the incidence of complete or partial DPD deficiency. The population comprised 152 men (mean age 62.1) and 33 women (mean age 59.2). Sixty eight were head and neck patients treated by a 5-day continuous infusion of 5-FU (starting dose 1 g/m2/day, with dose adaptation at mid-cycle) for which DPD activity was measured 2-3 days before 5-FU administration (94 cycles analyzed). DPD activity was measured by a radioenzymatic assay using 14C-5-FU. DPD activity showed a unimodal distribution, which globally fits a Gaussian distribution. Mean and median DPD activity were 0.222 and 0.211 nmol/min/mg prot respectively (range 0.065-0.559). No total DPD deficiency was found. Neither liver function nor age influenced DPD activity, but DPD activity was on average 15% lower in women than in men (0.194 and 0.228 nmol/min/mg prot respectively, p = 0.03). In patients treated with 5-FU, the risk of developing side effects was not linked to pretreatment DPD activity. 5-FU-related toxicity was linked to FU systemic exposure. The correlation between DPD activity and FU clearance was weak (n = 90, r = 0.31, p = 0.002). As a corollary, DPD activity in patients requiring a dose reduction was not significantly different from DPD activity in patients who did not require dose modification. From the present study it appears that total DPD deficiency is a very rare event. Although pre-treatment DPD activity cannot be a useful indicator for improving 5-FU dose adaptation strategy, the identification of partial DPD deficiency (< 0.100 nmol/min/mg prot, 3% of the population) could lead to starting the treatment with a markedly reduce 5-FU dose.
二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5-FU）分解代谢的初始酶。最近，淋巴细胞中疑似或确诊为DPD缺乏的患者出现严重和/或致命的5-FU相关毒性，这证明了DPD的临床重要性。我们对185例癌症患者进行了一项前瞻性研究，以评估完全或部分DPD缺乏的发生率。该人群包括152名男性（平均年龄62.1岁）和33名女性（平均年龄59.2岁）。68例为头颈部患者，接受5天连续输注5-FU治疗（起始剂量1 g/m²/天，在疗程中期调整剂量），在给予5-FU前2-3天测量DPD活性（分析94个疗程）。使用14C-5-FU通过放射酶法测量DPD活性。DPD活性呈单峰分布，总体符合高斯分布。DPD活性的平均值和中位数分别为0.222和0.211 nmol/min/mg蛋白（范围0.065-0.559）。未发现完全DPD缺乏。肝功能和年龄均不影响DPD活性，但女性的DPD活性平均比男性低15%（分别为0.194和0.228 nmol/min/mg蛋白，p = 0.03）。在接受5-FU治疗的患者中，出现副作用的风险与治疗前的DPD活性无关。5-FU相关毒性与FU全身暴露有关。DPD活性与FU清除率之间的相关性较弱（n = 90，r = 0.31，p = 0.002）。因此，需要降低剂量的患者的DPD活性与不需要调整剂量的患者的DPD活性无显著差异。从本研究来看，完全DPD缺乏是一种非常罕见的情况。虽然治疗前的DPD活性不能作为改善5-FU剂量调整策略的有用指标，但识别部分DPD缺乏（<0.100 nmol/min/mg蛋白，占人群的3%）可能会导致以显著降低的5-FU剂量开始治疗。
