Alkyl-lysophospholipids (ALP) are analogs of lysophophatidylcholine a new family of anticancer drugs which are cytocidal to neoplastic cells directly through disruption of the cell membrane or by activating macrophages to become cytocidal. There is evidence that some of these compounds selectively kill neoplastic cells and spare normal cells. Many neoplastic cells lack an O-alkyl cleavage enzyme, found in normal cells, which cleaves the other linkage catabolizing the compounds. Phospholipid biosynthesis and protein kinase C (PKC) activity are inhibited. Thus, the precise mechanism of action is unknown. The long term objectives of this project are to delineate the biochemical mechanisms responsible for the cytocidal effects through studies of the effect of various analogs of known structure on phospholipid biosynthesis and phospholipid regulators of growth and differentiation.
The specific aims are: 1) To better define the relationship between the chemical structure and cytocidal activity of different analogs against ALP sensitive and resistant leukemic cell lines, fresh human leukemic cells and normal bone marrow progenitor cells as measured by cell counts, dye exclusion, thymidine incorporation and clonogenicity; 2) To test the effect of ALP on phospholipid biosynthesis by measuring the dose-rate effect of incorporation of radiolabeled phospholipid precursors by intact cells and assays of specific enzymes in phospholipid biosynthesis; 3) To localize the site of action of ALPs within the cell be subcellular fractionation studies using Percoll density gradient centrifugation and biochemical markers; 4) To assess the role of the O-alkyl cleavage enzyme in the selective cytocidal activity of ALPs; 5) To study the mechanism of action of ALPs on PKC activity be investigating their effects on the phosphotransferase and phorbol ester binding activities of PKC, and their effects on phorbol ester-induced translocation of PKC in HL60 cells; and 6) To further investigate the inhibition by ALPs of the TPA-stimulated phosphorylation of endogenous proteins in intact sensitive and resistant cell lines. These studies should identify active analogs, aid in delineating the mechanism of action, detect selective differences between normal and neoplastic cells and add to our knowledge of mechanisms governing growth and differentiation.
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