The ceramide and sphingoid base backbones of sphingolipids are highly are highly bioactive compounds that affect growth, differentiation, cell migration and apoptosis when added to transformed cells in culture as well as when fed to mice treated when a colon carcinogen or that have a genetic that predisposes them to colon cancer. Based on the mechanisms of action of ceramides and sphingoid bases (and structure-function relationships for the metabolism of these compounds, synthetic analogs have been prepared that are more potent than the naturally compounds when tested against colon cancer cells in culture. This Program will characterize how these compounds are metabolized by cells in cultures and in vivo, as well as to evaluate the effectiveness of additional compounds that will be generated as part of a sphingolipid analog library.
The specific aims will be to: 1) Analyze sphingolipid analogs as substrates/inhibitors of specific enzymatic targets in vitro. 2) Analyze cellular metabolism/effects of the sphingolipid analogs. 3) Analyze sphingolipid analog digestion, uptake and metabolism in vivo. An, 4) Analyze selected sphingolipid analogs for their effects on tumors in animals models for cancer. The findings of these studies will identify the most effective compounds and strategies for use of sphingolipids for the prevention and treatment of colon cancer and, perhaps, other forms of neoplasia.
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