In order to determine the type of relationship which exists between gluconeogenesis inhibition at the phosphoenolpyruvate carboxykinase (PEP CK) reaction and tumor inhibition, the tumor-inhibiting effects of L-tryptophan, hydrazine sulfate and pyridine-2,3-dihydrazide – all known PEP CK inhibitors – were compared separately with their effects on: (a) the in vitro enzyme PEP CK; (b) gluconeogenesis in the isolated perfused rat liver, and (c) HeLa cell growth in culture. All substances were found to inhibit gluconeogenesis in the isolated perfused rat liver; the site of inhibition of l-tryptophan and hydrazine sulfate being PEP CK, as determined by previous cross-over studies. Both pyridine-2,3-dihydrazide and hydrazine sulfate inhibited the enzyme itself; l-tryptophan has no direct effect (its antigluconeogenic properties are due to metabolites). All three substances had virtually no effect on HeLa cells in culture, indicating a mechanism of in vivo antitumor action other than direct cytotoxicity. These data are consistent with a causal relationship existing between inhibition of gluconeogenesis at the PEP CK reaction and tumor inhibition. The overall mechanism of action is consistent with an inhibition of the energy loss expected from normal host cells of the body by virtue of recycling of many precursors to glucose via gluconeogenesis in the liver and kidney cortex. The actual mechanism of antitumor action per se is not yet known, though may be due to a cessation of glycolysis within the tumor itself, secondary to the accumulation of metabolic intermediates behind the PEP CK block.

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