We propose to continue and expand our studies on new ether lipid (EL) analogs of platelet activating factor as antineoplastic agents. These compounds inhibit malignant cells in three ways: by direct cytotoxic or cytostatic action, by macrophage activation, and by malignant cell differentiation. They are nonmutagenic and interact with the mammalian cell membrane and not with DNA. They are biochemical inhibitors of protein kinase C and of phosphatidylcholine biosynthesis. New analogs are designed, synthesized, and evaluated in this collaborative program. Biological evaluation includes inhibition of several malignant cells in vitro in cytotoxicity and clonogenic assays and in vivo in transplantable mouse tumors and in xenografts. Recent studies, which will be extended, include structure-activity correlations, combination chemotherapy studies, interaction with model membranes effects by electron spin resonance and by scanning and transmission electron microscopy. Photoactivatable and spin-labeled analogs will be prepared and investigated to extend these membrane studies. Pharmacokinetic studies of promising analogs will be done in mice. Other projects to be instituted include the potential of these ether lipid analogs as bone marrow purging agents and as an approach to circumvention of drug resistance through membrane alteration. The possibility that these compounds may regulate calcium homeostasis will be evaluated. Inhibition of protein kinase C and of other transmembrane signalling enzymes of the phosphatidylnositol cascade will be studied. Analogs will be identified with the greatest potency to activate human macrophages to the tumoricidal state. Selected analogs will be studied to determine their intracellular stability in human macrophages and its relationship to prolonging the activated state. the ability of the compounds to accelerate monocyte maturation, which may contribute to in vivo antitumor activity by increasing the number of mature tissue macrophages available for activation, will be examined.
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