ENERGY DEPLETION IN THE LIVER AND IN ISOLATED HEPATOCYTES OF TUMOR-BEARING ANIMALS

Cancer cachexia has a great impact on morbidity and mortality in patie nts undergoing surgery. Failure to maintain lean tissue against tumor- induced hypermetabolism results in cumulative weight loss and ultimate failure of the host. Cellular free energy is among the factors that r egulates metabolic pathways and may be altered in the tumor-bearing st ate. We studied in-vivo and in-vitro ATP levels and metabolic paramete rs in Fischer rats bearing a methylcholanthrene-induced sarcoma to elu cidate the energy state. Tissue ATP was measured in freeze-clamped liv er and muscle in 15 tumor-bearing rats (TBR) at different tumor burden s and their pair-fed controls (CTR) by bioluminescence assay. Plasma m etabolites, hormones, and enzymes were determined in the same animals. Liver ATP level was lower in TBR with a 5% tumor burden: 3.07 +/- 0.5 6 (SE) nmole/mg tissue vs CTR: 5.33 +/- 0.60 (P < 0.05), 10% TBR: 2.48 +/- 0.54 vs CTR: 4.05 +/- 0.63 (n.s.), and 20% TBR: 1.91 +/- 0.21 vs CTR: 3.86 +/- 0.40 (P < 0.01). Muscle ATP was not different between TB R and CTR. This progressive loss of liver ATP was associated with decr eased plasma insulin level (P < 0.001) and with increased alkaline pho sphatase level (P < 0.01) by multiple regression. In vitro, hepatocyte s were isolated from 8 TBR and 8 CTR by in-situ liver perfusion with c ollagenase and the cellular ATP was measured before and after 60 min i ncubation with glucogenic substrates. Hepatocytes from TBR decreased A TP by 42% (P < 0.05) in 10 mM lactate with higher gluconeogenesis, whi le control hepatocytes maintained the ATP. These results demonstrate a progressive loss of energy generating capacity in the tumor-bearing l iver with increased metabolic activity. Insulin resistance is postulat ed as a potential mechanism for these effects. (C) 1995 Academic Press , Inc.