Differences in metabolism of 5-fluorouracil and 5-fluorouridine and regulation by glucosamine in human colon cancer multicell tumor spheroids

Glucosamine (GlcN) modulates fluoropyrimidine metabolism and enhances cytot oxicity of 5-fluorouridine (FUrd), but not of 5-fluorouracil (FUra), in hum an tumor models. To elucidate the underlying metabolic differences between FUra and FUrd, by the use of F-19 and P-31 NMR spectroscopy we studied thes e drugs in multicell tumor spheroids (MTS) formed by human colon carcinoma cells HT-29. This experimental system allowed detailed kinetic measurements of anabolic intracellular phosphates and fluorophosphates over periods of up to 2 days. Time-dependent NMR data were reduced and interpreted by the u se of nonlinear compartmental models which yielded numerical values for the empirical rate constants characterizing mass transfer among the compartmen ts. An analysis of these rate constants indicated qualitative and quantitat ive differences in the metabolism of FUra and FUrd and in the effects of Gl cN on these drugs. The enhanced generation of FUDP-hexoses was a predicted effect of GlcN, but inhibited formation of fluorouridine diphosphates and f luorouridine triphosphates in FUra-treated MTS, and the magnitude of stimul ation of fluoropyrimidine incorporation into macromolecules in FUrd-treated MTS were not predicted, Copyright (C) 1999 John Wiley & Sons, Ltd.