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

Cancer cachexia has a great impact on morbidity and mortality in patients 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 regulates metabolic pathways and may be altered in the tumor-bearing state. We studied in-vivo and in-vitro ATP levels and metabolic parameters in Fischer rats bearing a methylcholanthrene-induced sarcoma to elucidate the energy state. Tissue ATP was measured in freeze-clamped liver and muscle in 15 tumor-bearing rats (TBR) at different tumor burdens and their pair-fed controls (CTR) by bioluminescence assay. Plasma metabolites, hormones, and enzymes were determined in the same animals. Liver ATP level was lower in TBR with a 5% tumor burden: 3.07 +/- 0.56 (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 TBR and CTR. This progressive loss of liver ATP was associated with decreased plasma insulin level (P < 0.001) and with increased alkaline phosphatase level (P < 0.01) by multiple regression. In vitro, hepatocytes were isolated from 8 TBR and 8 CTR by in-situ liver perfusion with collagenase and the cellular ATP was measured before and after 60 min incubation with glucogenic substrates. Hepatocytes from TBR decreased ATP by 42% (P < 0.05) in 10 mM lactate with higher gluconeogenesis, while control hepatocytes maintained the ATP. These results demonstrate a progressive loss of energy generating capacity in the tumor-bearing liver with increased metabolic activity. Insulin resistance is postulated as a potential mechanism for these effects. (C) 1995 Academic Press, Inc.