The effect of 6-aminonicotinamide on the metabolism of RIF-1 tumor cells was investigated using C and P NMR spectroscopy. 6-Aminonicotinamide can be metabolized to 6-amino-NAD(P), a competitive inhibitor of NAD(P)-requiring processes. 40 µM 6-aminonicotinamide led to an inhibition of 6-phosphogluconate dehydrogenase and an accumulation of 6-phosphogluconate. A subsequent accumulation of the 6-phosphogluconate precursor 6-phosphoglucono--lactone was observed in the C NMR spectrum. These metabolites were shown to be intracellular, although a small amount of leakage of 6-phosphoglucono--lactone occurred. The intracellular concentrations of 6-phosphogluconate and 6-phosphoglucono--lactone were 1.9 ± 0.8 µmol/10 cells (±1 standard deviation) and 0.8 ± 0.4 µmol/10 cells, respectively, after 15 h. Glucose utilization and lactate production were significantly inhibited by 6-aminonicotinamide (both p < 0.05), indicating inhibition of glycolysis. P NMR data showed that phosphocreatine was significantly depleted in cells exposed to 6-aminonicotinamide (p < 0.05). Exposure of RIF-1 cells to 6-aminonicotinamide prior to 3- or 6-Gy x-irradiation induced a supra-additive cell kill, indicating that 6-aminonicotinamide is acting as a radiosensitizer. There was no effect of 6-aminonicotinamide alone or when the drug was given postradiation, suggesting that its mechanism of action may be by inhibition of radiation-induced repair.

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