EARLY DETECTION OF CANCER CACHEXIA IN THE RAT USING P-31 MAGNETIC-RESONANCE SPECTROSCOPY OF THE LIVER AND A FRUCTOSE STRESS TEST

The dynamic metabolic effects of a fructose infusion challenge on hepa tic intracellular levels of adenosine 5'-triphosphate (ATP), inorganic phosphate (P-i) and phosphomonoesters (PME) were monitored noninvasiv ely by P-31 MRS in a remote tumour-bearing rat model. Fisher male rats were inoculated with a methylcholanthrene-induced sarcoma. Seventeen rats were randomized into three groups: control (n=6), low tumour burd en (LTB, n = 6), or moderate tumour burden (MTB, n = 5). The LTB group had tumour burdens of 0.2-2.0 % while the MTB group had tumour burden s of 2.6-5.7 %. All rats were in the pre-clinical phase of cancer cach exia as determined by food intake and body weight. Rats were infused w ith 1.2 g/kg of fructose i.v. and the metabolic response of the liver was monitored with time over 1 h via P-31 MRS. In all groups an immedi ate increase in hepatic levels of PME was noted, which returned to bas eline values over the course of the experiment, reflecting the phospho rylation of fructose to fructose 1-phosphate. For the MTB rats, the re turn to baseline levels was more rapid than in the control or LTB grou p. All groups experienced a 20% decrease in hepatic ATP levels which d id not return to baseline over the 1 h observation period. As well, al l groups experienced an initial fall in P-i, which recovered to prefru ctose levels or greater. MTB rats demonstrated a 30-40% increase in P- i concentration and a 60-70% increase in P-i/ATP ratio after infusion with fructose as compared to LTB and control rats (ANOVA; p < 0.05), T his is consistent with cachexia-induced enhancement of hepatic glucone ogenic activity, and hence more rapid release of P-i from the phosphor ylated metabolites in the MTB rats. Thus fructose infusion and hepatic P-31 MRS permit pre-clinical detection cancer cachexia as reflected b y increased P-i generation and more rapid removal of PME.