Effect of modulators on 5-fluorouracil metabolite patterns in murine colon carcinoma determined by in vitro 19F nuclear magnetic resonance spectroscopy.
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.
Kamm
V J
VJ
Department of Medical Oncology, University Hospital, Nijmegen, The Netherlands.
Rietjens
I M
IM
Vervoort
J
J
Heerschap
A
A
Rosenbusch
G
G
Hofs
H P
HP
Wagener
D J
DJ
D000818:Animals; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D005461:Fluorine; D005472:Fluorouracil / Q000378:metabolism*; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha; D005461:Fluorine; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate