In vivo and ex vivo study of metabolic and cellular effects of 5-fluorouracil chemotherapy in a mouse mammary carcinoma

Abstract

The effect of 5-fluorouracil (5FU) on the 31P nuclear magnetic resonance (NMR) profile of a mouse mammary carcinoma, implanted on the foot of CH3 He mice, was studied both in vivo and in perchloric acid extracts. In vivo, significant increases in the ratios, nucleotide triphosphate: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′) comprised 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 was due to an increase in the PE concentration rather than a decrease in PC. PE increased from 0.56 ± 0.11 μmol/g tissue in controls to 0.95 ± 0.29 μmol/g tissue 48 h after 5FU ( p < 0.006). Perchloric acid extracts also revealed a significant increase in phosphodiesters. Glycerophosphocholine increased from 0.82 ± 0.24 μmol/g tissue in controls to 1.82 ± 0.61 μmol/g tissue in 5FU treated tumors after 48 h ( p < 0.002), and glycerophosphoethanolamine increased from 0.25 ± 0.06 μmol/g tissue in controls to 0.36 ± 0.10 μmol/g tissue in treated tumors ( p < 0.004). These changes suggest that ethanolamine and choline containing metabolites in this tumor may be metabolized via different pathways. Cell cycle analysis showed only relatively small changes in cell cycle distribution and apoptotic fraction following 5FU.