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19 F NMR monitoring of in vivo tumor metabolism after biochemical modulation of 5‐fluorouracil by the uridine phosphorylase inhibitor 5‐benzylacyclouridine
Author(s) -
Holland Scott K.,
Bergman Andries M.,
Zhao Yiming,
Adams Earle R.,
Pizzorno Giuseppe
Publication year - 1997
Publication title -
magnetic resonance in medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.696
H-Index - 225
eISSN - 1522-2594
pISSN - 0740-3194
DOI - 10.1002/mrm.1910380609
Subject(s) - in vivo , fluorouracil , chemistry , metabolism , toxicity , nuclear magnetic resonance spectroscopy , uridine , pharmacology , floxuridine , biochemistry , biology , chemotherapy , medicine , rna , stereochemistry , microbiology and biotechnology , organic chemistry , gene
Abstract 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 19 F 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 (α‐fluoro‐β‐ureidopropionic acid and α‐fluoro‐β‐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. 19 F 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.