A pharmacologic research program is proposed to evaluate new alkyllysophospholipid (ALP) analogs of platelet activating factor (PAF) as potential clinical antitumor agents. In vitro experiments will identify ALP analogs with the greatest potency in activating human macrophages to the turmoricidal state and will be used to select ALP analogs with the most promise as effective antitumor agents in vivo. Metabolic studies of selected compounds in macrophages are intended to investigate the intracellular stability of ALP and its relationship to prolonging the activated state and the effects of ALP on macrophage lipid metabolism as it pertains to tumor cytotoxicity. ALP will also be investigated for the ability to accelerate monocyte maturation in vitro which may contribute to the in vivo antitumor activity by increasing the number of mature tissue macrophages available for activation. The possibility that the action of ALP on macrophage differentiation is mediated by effects on protein kinase C (PKC) will also be examined. The activity and distribution of PKC during macrophage activation and monocyte maturation induced by ALP will be determined. Inhibition of ovarian carcinoma cell lines in soft agar by these analogs will be studied at an early stage. Platelet aggregating activity of all analogs will be measured. Membrane interaction of several analogs will be studied by differential scanning calorimetry, spin-labelling, and photoaffinity binding. The in vivo experiments are intended to provide information on the toxicity of the compounds in normal mice, by several different routes of administration. Preliminary plasma pharmacokinetics will be carried out in order to quantitate plasma elimination (or retention) of the agent. In vivo antitumor studies will be done against the Ehrlich ascites tumor in CF1 mice by cytoreduction and prophylaxis experiments. This tumor was selected since a few ALP are active against it in chemotherapy trials. Other mouse tumor models will be studied. The establishment and study of the HL-60 human promyelocytic leukemic cell line in nude mice would provide an exciting investigative tool for comparison with our in vitro data with the HL-60 cell line. Should it prove difficult or impossible to establish the HL-60 cells in nude mice, recourse will be had to human ovarian carcinoma cell lines now being carried in cell culture at Bowman Gray. We will rely on the antitumor evaluation capabilities of DCT/NCI for more detailed antitumor studies and combination chemotherapy trials.
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