Molecular-metabolic imaging to determine metabolism-based therapeutic targets in hepatocellular carcinoma (HCC)
JOURNAL OF NUCLEAR MEDICINE(2012)
摘要
457 Objectives Metabolic activities of glucose, fatty acid, and glutamine play roles independently or complementarily in tumorigenesis. Inhibition to these metabolic activities could be a targeted therapeutic approach. In order to identify correlative molecular imaging markers against metabolism, we investigated the relationships between a) 18FDG/11C-acetate and glycolysis/lipogenesis, and b) 18FGln/18FDG and glutamine catabolism/glycolysis in Myc, MET, and AKT/Ras models of HCC. Methods Glucose and lactate levels, hexokinase (Hk2) activity, lipid accumulation using Oil Red O, and phosphate-dependent glutaminase activity were evaluated ex vivo. Percent injected dose per gram (%ID/g) of 18FDG, influx rate constant (Ki) of 11C-acetate using two-tissue compartment model, and influx (K1) and efflux (k2) rate constants of 18FGln using one-tissue compartment model were derived through in vivo PET. Results Glucose levels were low in all three tumors; however lactate levels were elevated only in Myc, associated with increased Hk2 activity, an isoform catalyzing the first step of glycolysis. Both Myc (n=5) and AKT/Ras (n=7) have higher 18FDG %ID/g (3.16±0.88 and 4.17±1.57) than MET (n=4) tumors (1.64±0.44). The Oil Red O assay showed no increased staining in MET, but marked staining in Myc and AKT/Ras. However, Myc (n=3), MET (n=4), and AKT/Ras (n=5) have higher 11C-acetate Ki (0.037±0.011, 0.035±0.005, and 0.054±0.015 min-1, respectively) than liver (n=6) (0.021±0.005 min-1). Glutaminase activities were significantly higher in Myc than MET, confirmed by K1 (0.37±0.13 vs. 0.14±0.06 min-1) and k2 (0.28±0.09 vs. 0.13±0.05 min-1) of 18FGln. Conclusions When the in vivo imaging data were compared against the biochemical metabolic data, the correlation between 18FGln influx/efflux rates and glutamine catabolism was the strongest
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