Etienne M C, Milano G, Fleming R A, Thyss A, Renée N, Schneider M, Demard F
Centre Antoine-Lacassagne, Nice, France.
Bull Cancer. 1992;79(12):1159-63.
We previously have shown that pharmacokinetic monitoring of 5-fluorouracil (5-FU) could significantly improve the 5-FU therapeutic index when given in continuous venous infusion (Br J Cancer 59, 287-290, 1989). However, the more rational approach would be to find individual biological factors which could predict 5-FU clearance. Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-FU. DPD activity was measured in 57 head and neck cancer patients receiving CDDP (100 mg/m2, day 1) plus 5-FU (1 g/m2/day x 5, day 2-day 6). DPD activity was measured in lymphocytes using a radioenzymatic assay (2.5 mM MgCl2, 250 microM NADPH, 20 microM 14C-5-FU) with separation of 14C-5-FU from 14C-5-FUH2 by HPLC coupled with a radiodetector. The average DPD activity measured in lymphocytes was 0.186 +/- 0.068 nmol/min/mg protein (range 0.058-0.357) and the average 5-FU clearance (Cl) was 2,523 +/- 684 ml/min/m2 (range 1,052-4,029). A significant linear correlation was demonstrated between DPD activity and 5-FU clearance (Cl = 1,099 + 7,580 DPD, r2 = 0.613, P < 0.0001). In patients evaluated for more than one cycle (n = 18), variations in 5-FU clearance were associated with corresponding variations in DPD activity. The individual determination of DPD activity measured in lymphocytes could be useful for identifying patients at risk for altered 5-FU pharmacokinetics and could be used to adjust the optimal 5-FU dose for each patient before starting the treatment.
我们之前已经表明，当连续静脉输注5-氟尿嘧啶（5-FU）时，对其进行药代动力学监测可显著提高5-FU的治疗指数（《英国癌症杂志》59, 287 - 290, 1989年）。然而，更合理的方法是找到能够预测5-FU清除率的个体生物学因素。二氢嘧啶脱氢酶（DPD）是5-FU分解代谢的初始酶。在57例接受顺铂（100 mg/m²，第1天）加5-FU（1 g/m²/天×5天，第2 - 6天）治疗的头颈癌患者中测量了DPD活性。使用放射酶法（2.5 mM氯化镁、250 microM烟酰胺腺嘌呤二核苷酸磷酸、20 microM 14C - 5-FU）在淋巴细胞中测量DPD活性，通过与放射性探测器联用的高效液相色谱法将14C - 5-FU与14C - 5-FUH2分离。在淋巴细胞中测得的平均DPD活性为0.186±0.068 nmol/分钟/毫克蛋白（范围0.058 - 0.357），平均5-FU清除率（Cl）为2523±684 ml/分钟/平方米（范围1052 - 4029）。DPD活性与5-FU清除率之间显示出显著的线性相关性（Cl = 1099 + 7580 DPD，r² = 0.613，P < 0.0001）。在接受多个周期评估的患者（n = 18）中，5-FU清除率的变化与DPD活性的相应变化相关。在淋巴细胞中测量的DPD活性的个体测定对于识别5-FU药代动力学改变风险的患者可能有用，并且可用于在开始治疗前为每位患者调整最佳5-FU剂量。
