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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 2 (ET)
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Emory University
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Hoffmann, D; Hoffmann, I (1997) The changing cigarette, 1950-1995. J Toxicol Environ Health 50:307-64
Vogler, W R; Shoji, M; Hayzer, D J et al. (1996) The effect of edelfosine on CTP:cholinephosphate cytidylyltransferase activity in leukemic cell lines. Leuk Res 20:947-51
Hoffmann, D; Rivenson, A; Hecht, S S (1996) The biological significance of tobacco-specific N-nitrosamines: smoking and adenocarcinoma of the lung. Crit Rev Toxicol 26:199-211
Vogler, W R; Berdel, W E; Geller, R B et al. (1996) A phase II trial of autologous bone marrow transplantation (ABMT) in acute leukemia with edelfosine purged bone marrow. Adv Exp Med Biol 416:389-96
Shoji, M; Fukuhara, T; Winton, E F et al. (1994) Different mechanisms of inhibition by alkyl-lysophospholipid and phorbol ester of granulocyte-macrophage colony-stimulating factor binding to human leukemic cell lines. Exp Hematol 22:13-8
Zheng, B; Chambers, T C; Raynor, R L et al. (1994) Human leukemia K562 cell mutant (K562/OA200) selected for resistance to okadaic acid (protein phosphatase inhibitor) lacks protein kinase C-epsilon, exhibits multidrug resistance phenotype, and expresses drug pump P-glycoprotein. J Biol Chem 269:12332-8
Okabe, M; Kawamura, K; Miyagishima, T et al. (1994) Effect of herbimycin A, an inhibitor of tyrosine kinase, on protein tyrosine kinase activity and phosphotyrosyl proteins of Ph1-positive leukemia cells. Leuk Res 18:213-20
Candal, F J; Bosse, D C; Vogler, W R et al. (1994) Inhibition of induced angiogenesis in a human microvascular endothelial cell line by ET-18-OCH3. Cancer Chemother Pharmacol 34:175-8
Vogler, W R; Olson, A C; Hajdu, J et al. (1993) Structure-function relationships of alkyl-lysophospholipid analogs in selective antitumor activity. Lipids 28:511-6
Raynor, R L; Kim, Y S; Zheng, B et al. (1992) Membrane interactions of mastoparan analogues related to their differential effects on protein kinase C, Na, K-ATPase and HL60 cells. FEBS Lett 307:275-9

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