Cytotoxicity of ether-linked phytanyl phospholipid analogs and related derivatives in human HL-60 leukemia cells and...

A cytotoxic activity, highly selective for neoplastic cells, is expressed by 1-alkyl-2-methoxy-sn-glycero-3-phosphocholine and by other derivatives closely related to the chemical structure of platelet activating factor. The antineoplastic potencies of a new series of analogs tested in HL-60 human leukemia cells and human polymorphonuclear neutrophils are reported. The degree of cytotoxicity was documented according to the ability of each analog to 1) destroy leukemic or normal cells or 2) to release lactic acid dehydrogenase from these cells. An index of selectivity of the analogs for their cytotoxicity toward leukemia cells is presented. Substitution by the twenty carbon branched-chain phytanyl moiety in place of the straight chain alkyl ether-linked group at the sn-1 position of various phospholipid analogs resulted in a 3- to 10-fold reduction in their cytotoxic potency in HL-60 leukemia cells. The enantiomeric isomers (D-forms) of several of the analogs possessed slightly greater phospholipid analogs possessing the sn-2-acetyl (platelet activating factor) or sn-2- propionoyl substituents, both biologically active in their ability to aggregate platelets and to induce hypotension, were relatively innocuous in terms of the measured cytotoxic responses in both HL-60 cells and neutrophils.