Our recent 31P NMR studies of lymphomas in vivo and of chronic lymphocytic leukemic cells in vitro show that human B-lymphoid malignancies have a patter of phospholipid metabolites characterized by a high ratio of phosphoethanolamine to phosphocholine and very low amounts of glycerophosphoethanolamine and glycerophosphocholine. We hypothesize that this pattern results in large part from a sustained activation of one or more phospholipases C or D acting on phosphatidylethanolamine (PE). We have observed further that an early treatment-induced decrease in the phosphoethanolamine signal intensity predicts response of an individual lymphoma to whatever treatment was initiated. We hypothesize that this phenomenon is a manifestation of the susceptibility of the lymphoma cells to undergo treatment-induced apoptosis, and that it reflects the modulation of a process specific for PE metabolism. We propose to test these hypotheses using 3 different human B-lymphoid malignancy cell lines which are models of the grades of NHL found in vivo. They will be studied under conditions in which their phospholipid metabolite pattern resembles that of lymphomas in vivo. The hypothesis that these cells have sustained activation of a phospholipase C or D will be tested by examining catabolism of radiolabelled phospholipids, and aspects of phospholipid synthesis will be examined in NMR studies of perfused cells. The effects of treatment- induced apoptosis on phospholipid synthesis and degradation will be studied using these techniques along with 31P NMR spectroscopy. This Project interacts closely with the Chemistry Core in the exchange of developing techniques and insights. The results of this project should provide a better understanding of the biochemical and biological bases for the phospholipid metabolic characteristics of lymphomas observed in vivo in clinical settings.
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