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Effect of Modulators on 5-Fluorouracil Metabolite Patterns in Murine Colon Carcinoma Determined by in Vitro ¹⁹F Nuclear Magnetic Resonance Spectroscopy¹

Departments of Medical Oncology [Y. J. L. K., H. P. H., D. J. T. W.] and Radiodiagnostics [A. H., G. R.], University Hospital, P. O. Box 9101, 6500 HB Nijmegen, and Department of Biochemistry, Agricultural University, Wageningen [I. M. C. M. R., J. V.], the Netherlands

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 -fluoro-ß-ureidopropionic acid and -fluoro-ß-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); -interferon (10⁵ 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), -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.

¹ This work was supported by the Dutch Cancer Society.

² To whom requests for reprints should be addressed.

Received 9/27/93. Accepted 6/ 8/94.