Effect of modulators on 5-fluorouracil metabolite patterns in murine colon carcinoma determined by in vitro 19F nuclear magnetic resonance spectroscopy.

Abstract

High-resolution 19F nuclear magnetic resonance spectroscopy at 7 T was used to study the effect of modulators on the metabolism of 5-fluorouracil (5-FUra, 115 mg/kg i.p.) in C38 murine colon tumors grown in C57BL/6 mice. Distinct 5-FUra metabolite patterns were found in perchloric acid extracts of these tumors after treatment. The 19F nuclear magnetic resonance spectra exhibited resonances representing 5-FUra, the catabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine, as well as four distinct fluoronucleotide anabolites. Using this model system the effect of several modulators on 5-FUra tumor metabolite patterns was investigated: methotrexate (300 mg/kg); alpha-interferon (10(5) IU/animal); N-(phosphonacetyl)-L-aspartate (100 and 250 mg/kg); and leucovorin (300 and 750 mg/kg). A significant increase in the anabolite:catabolite ratio was observed for the groups treated with 5-FUra in combination with the modulators methotrexate (n = 8), alpha-interferon (n = 7), and high-dose leucovorin (n = 14), but not for low-dose leucovorin (n = 7). Cotreatment with high-dose N-(phosphonacetyl)-L-aspartate (n = 8) resulted in a significant decrease in the anabolite: catabolite ratio compared to treatment with 5-FUra alone (n = 16). Possible correlations of metabolite profiles with therapy response are discussed.