F-19 NMR monitoring of in vivo tumor metabolism after biochemical modulation of 5-fluorouracil by the uridine phosphorylase inhibitor 5-benzylacyclouridine

A uridine phosphorylase inhibitor, 5-benzylacyclouridine (BAU), has been utilized as biochemical modulator of 5-fluorouracil (5-FU) anti-tumor activity in a murine tumor model, The effect of BAU on 5-FU metabolism has been evaluated using in vitro and in vivo F-19 NMR spectroscopy. The analysis of the NMR data revealed an increased formation and retention of fluorouracil nucleotides and fluorouridine in colon 38 tumors treated with the regimen containing BAU and a reduction in 5-FU catabolites (alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine). In the normal tissues evaluated, the presence of BAU did not significantly alter the metabolism and presence of fluoropyrimidine species, indicating a more selective effect on tumor tissues. Therapy experiments on C57/BL6 mice bearing colon 38 tumor showed that the administration of 120 mg/kg BAU 30 min before 5-FU at 85 mg/kg, on a weekly basis, resulted in an increased antineoplastic effect compared to the same dose of 5-FU alone, A smaller dose of 5-FU (60 mg/kg) also administered 30 min after 120 mg/kg BAU caused a reduction in tumor growth similar to 5-FU alone, The addition of BAU to 5-FU (85 mg/kg) resulted in a slight increase, although statistically nonsignificant, in host toxicity without causing any toxic death during the chemotherapeutic treatment, F-19 NMR spectroscopy is here shown to be a powerful technique to evaluate changes in the metabolism of fluoropyrimidines after the use of biochemical modulator and to allow a correlation between improved therapeutic response with the biochemical effects generated in tissues.