Cyclophosphamide augments the anti-tumor efficacy of uracil and tegafur by inhibiting dihydropyrimidine dehydrogenase.

The present study assesses the effects of neo-adjuvant chemotherapy (NAC) with uracil and tegafur (UFT) alone vs UFT plus cyclophosphamide (CPA), on the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in breast cancer tissues. Breast cancer patients were randomly assigned to 3 groups; the control (no-treatment) group (n=13), the UFT (5-8 mg/kg/day) alone group (n=10) and the UFT plus CPA (1 mg/kg/one day interval) (UC) group (n=9), and they received NAC for 2-4 weeks. A total of 32 invasive ductal breast carcinomas were used to assay for TS and DPD activity. There were no statistically significant differences in tumor size or stage classification between the 3 groups. The DPD activity was inversely and significantly correlated with the tumor size and pT, but the TS activity was not correlated with these clinicopathological factors. The TS activity was decreased by NAC with UFT, and the addition of CPA resulted in an increased inhibition of TS activity. In contrast, DPD activity was increased by NAC with UFT administration, but its increased activity was significantly inhibited by the addition of CPA. Multiple regression analyses demonstrated that the total dose of UFT was a significant variable for inhibiting TS activity, and that CPA was a significant variable for inhibiting DPD activity. The DPD activity increased by UFT can be inhibited by CPA, and this may represent one of the possible mechanisms responsible for the anti-tumor activity of 5-FU or its derivatives as enhanced by CPA.