Putative Role of Dihydropyrimidine Dehydrogenase in the Toxic Side Effect of 5-Fluorouracil in Colorectal Cancer Patients

Abstract

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/10⁶ lymphocytes); medium (DPD = 5.04–13.25 pmol/min/10⁶ lymphocytes), and high (DPD > 13.26 pmol/min/10⁶ 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.

Quantitation of Dihydropyrimidine Dehydrogenase Expression by Real-Time Reverse Transcription Polymerase Chain Reaction

“…To date, more than 20 profoundly DPDdeficient cancer patients who developed life-threatening toxicity following exposure to 5-FU (7-10) have been identified. The frequent use of 5-FU in cancer chemotherapy, the critical role of DPD in 5-FU pharmacokinetics, and the increasing number of reported DPD-deficient cancer patients have led some researchers to conclude that DPD enzyme activity should be determined in patients prior to treatment with 5-FUbased chemotherapy (7,11,12).…”

Enzyme-Catalyzed Activation of Anticancer Prodrugs

“…Ftorafur avoids the rapid breakdown of 5-FU in the gastrointestinal tract. 5-FU inhibits the growth of cancer cells by thymidylate synthase inhibition and by incorporation into DNA and RNA (Au and Sadee, 1981;Katona et al, 1998). Ftorafur is activated to 5-FU by both cytosolic thymidine phosphorylase and microsomal P450s (Kawata et al, 1984;Sugata et al, 1986;Komatsu et al, 2001).…”

Individualization of 5-Fluorouracil in the Treatment of Colorectal Cancer

“…In a prospective study of 48 patients with colorectal cancer who were receiving 5-FU and leucovorin as adjuvant therapy after surgery, DPD activity in lymphocytes correlated with 5-FU-related toxicity [48]. Nine (82%) of the 11 patients with low DPD activity experienced 5-FU-related side effects (e.g., mucositis, diarrhoea, myelotoxicity, angina pectoris, hypertension).…”