19F 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 19F 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. 19F 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.
Holland
S K
SK
Department of Radiology, Children's Hospital Medical Center, University of Cincinnati, Ohio, USA.
Bergman
A M
AM
Zhao
Y
Y
Adams
E R
ER
Pizzorno
G
G
D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005462:Fluorine Radioisotopes; D005472:Fluorouracil / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000378:metabolism*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; C034753:5-benzylacyclouridine; D014498:Uracil; D014543:Uridine Phosphorylase; D005472:Fluorouracil