Ether lipids (EL) represent a new family of unique antineoplastic compounds entering clinical trials which target the cell membrane as their primary site of action. Furthermore, they appear to be selectively cytocidal to neoplastic cells and spare normal bone marrow progenitor cells. Inhibition of phospholipid biosynthesis, protein kinase C (PKC) and Na+,K+-ATPase (sodium pump) activities are among the observations relative to the mechanisms of the inhibitory action. The long term objectives of this proposal are to delineate the biochemical mechanisms responsible for the selective cytotoxicity to neoplastic tissues through studies utilizing EL analogs of defined structures to perturb metabolic pathways of phospholipid biosynthesis, regulators of cell proliferation and the processes of differentiation.
The specific aims are by comparing sensitive and resistant cell lines to: 1) trace the uptake of radiolabeled EL into the cell, its intracellular distribution and its metabolic fate; 2) observe differences of EL effects upon enzymatic synthesis and catabolism of membrane phospholipids, especially phosphatidylcholine synthesis, and phospholipase C and D and their products; 3) examine the role of PKC and the Na+,K+-ATPase (sodium pump) in leukemic cell differentiation, proliferation and endogenous protein phosphorylation after perturbing these systems with EL and related analogs; and the specific aim which makes the above studies imperative; 4) complete a phase I clinical trial using EL as a purging agent for acute leukemic patients undergoing autologous bone marrow transplantation.
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