DECREASED DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITY IN A POPULATION OFPATIENTS WITH BREAST-CANCER - IMPLICATION FOR 5-FLUOROURACIL-BASED CHEMOTHERAPY

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting en zyme in the catabolism of fi-fluorouracil (5-FU), one of the most wide ly used chemotherapeutic agents in the treatment of breast cancer, The objective of this study was to determine the population characteristi cs of DPD activity in patients with breast cancer as well as the frequ ency of DPD deficiency in this population, DPD activity in peripheral blood mononuclear cells (PBM-DPD) was determined in 360 patients with breast cancer, with the mean PBM-DPD (0.26 +/- 0.01 nmol/min/mg protei n) being significantly lower than that observed in female controls (0. 44 +/- 0.02 nmol/min/mg protein; P < 0.01), ANOVA analysis examining t he significance of differences in DPD activity among various groups in dicated that only disease difference (breast cancer versus normal subj ects) was significant after adjustments for race and age, In the prese nt study, 21 (5.8%) patients were considered to be DPD deficient, indi cating that this pharmacogenetic syndrome may be more common than anti cipated (no DPD-deficient individual was found in the controls). Signi ficantly lower DPD activity in patients with breast cancer may predisp ose to 5-FU-associated toxicity, These results provide further rationa le for individualizing the 5-FU dose, thus reducing the risk of toxici ty and/or improving therapeutic efficacy in patients with breast cance r.