Prediction of 5-fluorouracil cytotoxicity towards the walker carcinosarcoma using peak integrals of fluoronucleotides measured by MRS in vivo

Abstract

19F-magnetic resonance spectroscopy (MRS) can be used to non-invasively monitor metabolism of 5-fluorouracil (5FU) to cytotoxic fluoronucleotides (FNuct). We investigated whether the levels of FNuct formed from 5FU and observed in vivo by MRS in the Walker carcinosarcoma predicted cytotoxicity. Fifty mgkg-1 5FU caused tumour FNuct formation and, when repeated daily for 1 week, significant tumour growth inhibition (P<5%). Twenty-five mgkg‑1 5FU produced less tumour FNuct (P<5%) and did not cause significant tumour regression. Tumour regression and tumour FNuct formation were also suppressed by 50mgkg‑1 5FU combined with a molar equivalent dose of allopurinol (P<2%). Tumour extracts were analysed by hplc and MRS confirming the observations in vivo and demonstrating that peak integrals in vivo were directly proportional to 5FU and FNuct concentrations. Hplc analysis of extracts showed that 50% of FNuct in tumours treated with 5FU was the cytotoxic nucleotide FUTP; this was lowered to 5% by a molar equivalent dose of allopurinol (P<2%). Twenty-five mgkg‑1 5FU also produced significantly less FUTP (36%) than the 50mgkg‑1 dose (P<5%). These results suggest that MRS-detectable changes in tumour FNuct (mostly in FUTP) can be used to predict 5FU cytotoxicity. © The Macmillan Press Ltd., 1989.