Etienne M C, Lagrange J L, Dassonville O, Fleming R, Thyss A, Renée N, Schneider M, Demard F, Milano G
Centre Antoine Lacassagne, Nice, France.
J Clin Oncol. 1994 Nov;12(11):2248-53. doi: 10.1200/JCO.1994.12.11.2248.
We conducted a prospective study on a large set of cancer patients in an attempt to evaluate the incidence of complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency as found in peripheral mononuclear cells (PMNC).
One hundred eighty-five unselected consecutive cancer patients were included. The population consisted of 152 men (mean age, 62.1 years; range, 35 to 90) and 33 women (mean age, 59.2 years; range, 36 to 77). Sixty-eight were head and neck patients treated by a 5-day continuous infusion of fluorouracil (FU; starting dose, 1 g/m2/d, with dose adaptation based on pharmacokinetics) for which DPD activity was measured 2 to 3 days before FU administration (94 cycles analyzed). PMNC-DPD activity was measured by a radio-enzymatic assay using carbon-14-FU.
DPD activity in the entire population showed a unimodal distribution, which globally fits a gaussian distribution. Mean and median DPD activity values were 0.222 and 0.211 nmol/min/mg protein, respectively (range, 0.065 to 0.559). No total DPD deficiency was found. Multifactor analysis of variance showed that liver function (biologic evaluation) and age did not influence DPD activity, but that DPD activity was, on average, 15% lower in women (0.194 nmol/min/mg protein) than in men (0.228 nmol/min/mg protein) (P = .03). No difference was demonstrated between premenopausal and postmenopausal women. In patients treated with FU, the risk of developing side effects was not linked to pretreatment DPD activity. FU-related toxicity was linked to FU systemic exposure. The correlation between pretreatment DPD activity and FU systemic clearance (CI) was weak (n = 90, linear regression r = .31, P = .002). Pretreatment DPD activity in patients who required 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 rare event. Although pretreatment DPD activity cannot be a useful indicator for improving FU dose adaptation strategy, the identification of severe DPD deficiency (< 0.100 nmol/min/mg protein) could lead to starting the treatment with a markedly reduced FU dose or even to using an alternative chemotherapy regimen.
我们对一大组癌症患者进行了一项前瞻性研究，以评估在外周血单核细胞（PMNC）中发现的完全或部分二氢嘧啶脱氢酶（DPD）缺乏的发生率。
纳入了185例未经选择的连续癌症患者。该人群包括152名男性（平均年龄62.1岁；范围35至90岁）和33名女性（平均年龄59.2岁；范围36至77岁）。68例头颈部患者接受了为期5天的氟尿嘧啶（FU）持续输注治疗（起始剂量1 g/m²/d，并根据药代动力学调整剂量），在FU给药前2至3天测量DPD活性（分析了94个周期）。使用碳-14-FU通过放射酶法测量PMNC-DPD活性。
整个人群的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至0.559）。未发现完全DPD缺乏。多因素方差分析表明，肝功能（生物学评估）和年龄不影响DPD活性，但女性的DPD活性平均比男性低15%（0.194 nmol/min/mg蛋白对0.228 nmol/min/mg蛋白）（P = 0.03）。绝经前和绝经后女性之间未显示出差异。在接受FU治疗的患者中，出现副作用的风险与治疗前DPD活性无关。FU相关毒性与FU全身暴露有关。治疗前DPD活性与FU全身清除率（CI）之间的相关性较弱（n = 90，线性回归r = 0.31，P = 0.002）。需要降低剂量的患者的治疗前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，似乎完全DPD缺乏是一种罕见情况。虽然治疗前DPD活性不能作为改进FU剂量调整策略的有用指标，但识别严重DPD缺乏（<0.100 nmol/min/mg蛋白）可能导致以显著降低的FU剂量开始治疗，甚至使用替代化疗方案。
