Individualizing therapy with 5-fluorouracil related to dihydropyrimidine dehydrogenase: Theory and limits

5-Fluorouracil (FU) is metabolized by dihydropyrimidine dehydrogenase (DPD). Patients with suspected or proven DPD deficiency develop more or less severe FU-related side effects including death. In these reported cases, DPD activity in peripheral blood mononuclear cells (PBMC-DPD) was < 100 pmol/min/mg protein. A circadian rhythm in PBMC-DPD activity has been observed, with a peak at 1 a.m. and a trough at 1 p.m. on average. As a corollary, a circadian rhythm was observed in FU plasma concentration, with a peak at 11 a.m. and a trough at 11 p.m. on average. A significant relationship between PBMC-DPD activity and FU clearance was established but the link was weak (r = 0.31). Thus, a FU dose adaptation based on PBMC-DPD is not justified whereas a pharmacokinetically based FU dose adaptation is recommended. Experimental studies have shown that DPD activity in tumor cell lines is related to FU cytotoxicity. Although resistance to FU depends on many factors, recent clinical studies in head and neck cancer patients treated by FU suggest that tumoral DPD activity is a determining factor in predicting FU-responsiveness.