Abstract
Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.
MeSH terms
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Animals
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / enzymology
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Glucosephosphate Dehydrogenase / metabolism
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Humans
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In Vitro Techniques
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Ketoglutarate Dehydrogenase Complex / metabolism
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Magnetic Resonance Spectroscopy
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Mice
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Mice, Nude
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Molecular Structure
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Oxythiamine / antagonists & inhibitors
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Phosphorylation / drug effects
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Spleen / drug effects
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Spleen / enzymology
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Structure-Activity Relationship
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Thiamine / analogs & derivatives*
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Thiamine / antagonists & inhibitors*
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Transketolase / antagonists & inhibitors*
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Xenograft Model Antitumor Assays
Substances
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Enzyme Inhibitors
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Oxythiamine
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Glucosephosphate Dehydrogenase
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Ketoglutarate Dehydrogenase Complex
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Transketolase
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Thiamine