IN-VIVO AND EX-VIVO STUDY OF METABOLIC AND CELLULAR EFFECTS OF 5-FLUOROURACIL CHEMOTHERAPY IN A MOUSE MAMMARY-CARCINOMA

The effect of 5-fluorouracil (5FU) on the P-31 nuclear magnetic resona nce (NMR) profile of a mouse mammary carcinoma, implanted on the foot of CH3/He mice, was studied both in vivo and in perchloric acid extrac ts. In vivo, significant increases in the ratios, nucleotide triphosph ate:inorganic phosphate (P-i) (p < 0.02) and phosphocreatine:P-i (p < 0.005), were observed 48 h after 5FU, relative to control. Two readily resolvable peaks were observed in the phosphomonoester region of the in vivo NMR spectrum, phosphocholine (PC) and a peak (denoted PME') co mprised of mainly phosphoethanolamine (PE). PME':PC was significantly elevated relative to control from 24 h to 168 h (p < 0.0001 at 48 h). Perchloric acid extract data indicate that the change in this ratio wa s due to an increase in the PE concentration rather than a decrease in PC. PE increased from 0.56 +/- 0.11 mu mol/g tissue in controls to 0. 95 +/- 0.29 mu mol/g tissue 48 h after 5FU (p < 0.006). Perchloric aci d extracts also revealed a significant increase in phosphodiesters. Gl ycerophosphocholine increased from 0.82 +/- 0.24 mu mol/g tissue in co ntrols to 1.82 +/- 0.61 mu mol/g tissue in 5FU treated tumors after 48 h (p < 0.002),and glycerophosphoethanolamine increased from 0.25 +/- 0.06 mu mol/g tissue in controls to 0.36 +/- 0.10 mu mol/g tissue in t reated tumors (p < 0.004). These changes suggest that ethanolamine and choline containing metabolites in this tumor may be metabolized via d ifferent pathways. Cell cycle analysis showed only relatively small ch anges in cell cycle distribution and apoptotic fraction following 5FU. (C) 1997 Elsevier Science Inc.