Metz-Kurschel U, Kurschel E, Wagner K, Aulbert E, Graben N, Philipp T
Department of Renal and Hypertensive Diseases, University Medical School, Essen, FRG.
Ren Fail. 1990;12(2):93-7. doi: 10.3109/08860229009087124.
High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One of the mechanisms of action of 5-FU is its conversion into fluorodeoxyuridylate (FdUMP), which inhibits thymidilate synthetase (TS). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid. On the other hand, it is well known that treatment of animals with high doses of folinic acid results in acute renal failure due to tubular obstruction. In order to find out whether there are similar findings in the clinical setting, we investigated 8 patients (pts.) with metastatic gastrointestinal cancer who were treated with this chemotherapy. We used the following parameters: 1. excretion of four urinary enzymes (LDH, LAP, GGT, NAG); 2. creatinine clearance on days 1 and 5. Therapy consisted of folinic acid 200 mg/m2 i.v. on days 1-5 and 5-fluorouracil 400 mg/m2 on days 1-5. Each treatment cycle was repeated on day 28. We found a constant decrease in the excretion of all 4 enzymes from normal to subnormal values which was statistically significant (p less than .05) during the two treatment cycles. Creatinine clearance decreased about 50% in three patients from normal initial values. In conclusion, during therapy with high-dose folinic acid and 5-fluorouracil we found signs of tubular damage which are similar to those found in folate nephropathy.
高剂量亚叶酸与5-氟尿嘧啶（5-FU）联合使用是一种用于治疗转移性胃肠道癌的新型联合化疗方法。5-FU的作用机制之一是其转化为氟脱氧尿苷酸（FdUMP），后者可抑制胸苷酸合成酶（TS）。亚叶酸浓度的增加会提高TS的抑制率。另一方面，众所周知，给动物高剂量注射亚叶酸会因肾小管阻塞导致急性肾衰竭。为了弄清楚在临床环境中是否有类似的发现，我们对8例接受这种化疗的转移性胃肠道癌患者进行了调查。我们使用了以下参数：1. 四种尿酶（乳酸脱氢酶、亮氨酸氨基肽酶、γ-谷氨酰转移酶、N-乙酰-β-D-氨基葡萄糖苷酶）的排泄情况；2. 第1天和第5天的肌酐清除率。治疗方案为第1 - 5天静脉注射亚叶酸200mg/m²，第1 - 5天静脉注射5-氟尿嘧啶400mg/m²。每个治疗周期在第28天重复。我们发现，在两个治疗周期中，所有4种酶的排泄量持续从正常水平降至低于正常水平，且具有统计学意义（p < 0.05）。3例患者的肌酐清除率从初始正常水平下降了约50%。总之，在高剂量亚叶酸与5-氟尿嘧啶联合治疗期间，我们发现了肾小管损伤的迹象，这与叶酸肾病中发现的迹象相似。
