PUTATIVE ROLE OF DIHYDROPYRIMIDINE DEHYDROGENASE IN THE TOXIC SIDE-EFFECT OF 5-FLUOROURACIL IN COLORECTAL-CANCER PATIENTS

Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting e nzyme in the catabolism of 5-fluorouracil (5-FU). It has been reported from various laboratories that the plasma concentration of 5-FU was i nfluenced 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, DP D activity was determined in the lymphocytes of 48 patients with color ectal cancer after surgery during the therapeutic course with 5-FU and folinic acid. On the basis of the enzyme activity, patients were divi ded 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 follo wing results were obtained. In the low DPD activity group, 9 of 11 pat ients had 5-FU-related side effects (mucositis, diarrhea, myelotoxicit y, angina pectoris, hypertension). In 3 patients, no change of the the rapy was needed, in 3 patients symptoms could be reversed by dose redu ction of 5-FU while in 3 patients interruption of 5-FU therapy was nee ded. In the medium DPD activity group, mild toxicity (diarrhea, transi tory 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 ef fects 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 individua lly.