Katona C, Kralovánszky J, Rosta A, Pandi E, Fónyad G, Tóth K, Jeney A
First Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary.
Oncology. 1998 Sep-Oct;55(5):468-74. doi: 10.1159/000011897.
Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme in the catabolism of 5-fluorouracil (5-FU). It has been reported from various laboratories that the plasma concentration of 5-FU was influenced by DPD activities in various normal human organs (e.g. liver or lymphocytes). Since the congenital deficiency in DPD caused severe, in some cases lethal, FU-related toxicity, it was decided to collect data about the DPD activity in colorectal cancer patients in order to investigate the possible correlation between the enzyme activity and appearance of the side effects of 5-FU. Assuming that DPD activity in lymphocytes represents the 5-FU catabolic capacity of the organism, DPD activity was determined in the lymphocytes of 48 patients with colorectal cancer after surgery during the therapeutic course with 5-FU and folinic acid. On the basis of the enzyme activity, patients were divided into three categories: low (DPD <5.03 pmol/min/10(6) lymphocytes); medium (DPD = 5.04-13.25 pmol/min/10(6) lymphocytes), and high (DPD > 13.26 pmol/min/10(6) lymphocytes) activity groups. By evaluating the toxic side effects during the 5-FU + folinic acid treatment, the following results were obtained. In the low DPD activity group, 9 of 11 patients had 5-FU-related side effects (mucositis, diarrhea, myelotoxicity, angina pectoris, hypertension). In 3 patients, no change of the therapy was needed, in 3 patients symptoms could be reversed by dose reduction of 5-FU while in 3 patients interruption of 5-FU therapy was needed. In the medium DPD activity group, mild toxicity (diarrhea, transitory hypertension) occurred in 5 of 29 and in the high activity group (diarrhea) in 1 of 8 patients, respectively. In these last two groups, no dose reduction of 5-FU was necessary. The present study furnished further evidence for the possible correlation between the 5-FU side effects and DPD function. Consequently, it is recommended to measure DPD activity prior to 5-FU based chemotherapy, which might be helpful in avoiding drug-related toxicity by adjusting the dose of 5-FU individually.
二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5-FU）分解代谢中的首个限速酶。多个实验室报告称，5-FU的血浆浓度受人体各正常器官（如肝脏或淋巴细胞）中DPD活性的影响。由于先天性DPD缺乏会导致严重的、在某些情况下甚至致命的与FU相关的毒性反应，因此决定收集有关结直肠癌患者DPD活性的数据，以研究酶活性与5-FU副作用出现之间的可能关联。假设淋巴细胞中的DPD活性代表机体的5-FU分解代谢能力，对48例接受5-FU和亚叶酸治疗的结直肠癌术后患者的淋巴细胞进行了DPD活性测定。根据酶活性，将患者分为三类：低活性组（DPD<5.03 pmol/min/10(6)淋巴细胞）；中活性组（DPD = 5.04 - 13.25 pmol/min/10(6)淋巴细胞）和高活性组（DPD>13.26 pmol/min/10(6)淋巴细胞）。通过评估5-FU +亚叶酸治疗期间的毒副作用，得到了以下结果。在低DPD活性组中，11例患者中有9例出现了与5-FU相关的副作用（粘膜炎、腹泻、骨髓毒性、心绞痛、高血压）。3例患者无需改变治疗方案，3例患者通过降低5-FU剂量症状得以缓解，3例患者则需要中断5-FU治疗。在中DPD活性组中，29例患者中有5例出现轻度毒性反应（腹泻、短暂性高血压），在高活性组中，8例患者中有1例出现腹泻。在这后两组中，无需降低5-FU剂量。本研究为5-FU副作用与DPD功能之间的可能关联提供了进一步证据。因此，建议在基于5-FU的化疗前测定DPD活性，这可能有助于通过个体化调整5-FU剂量来避免药物相关毒性。
