CYTO-TOXICITY OF PLATELET ACTIVATING FACTOR AND RELATED ALKYL-PHOSPHOLIPID ANALOGS IN HUMAN-LEUKEMIA CELLS, POLYMORPHONUCLEAR NEUTROPHILS, AND SKIN FIBROBLASTS

Abstract

A series of 11 alkyl-phospholipid analogs, structurally related to platelet activating factor (L-PAF), were analyzed for cytotoxic activity in human leukemic (HL-60) cells, human polymorphonuclear neutrophils and Detroit 551 human skin fibroblasts. The order of selectiveness of the analogs in their cytotoxic response toward HL-60 cells in comparison to neutrophils is 1-alkyl-2-acetamide-GPC [glycerophosphocholine moiety] > 1-alkyl-2-methoxy-GPC > D-PAF > 1-acyl-2-lyso-GPC > 1-alkyl-2-lyso-GPC > L-PAF. A time-sequenced progression of events caused by the most potent cytotoxic alkyl-phospholipid analogs was characterized by a rapid decrease in the cellular uptake and incorporation of 3H-thymidine into DNA that was detectable 4 h after exposure to the analog, a release of lactate dehydrogenase activity into the media at 8 h after exposure, and a decrease in cell number due to cell death that begins at 12 h after exposure. Treatment of HL-60 cells with 1-alkyl-2-methoxy-GPC for 1 h destroyed 40% of the cells after a subsequent 24-h incubation period. The varied biologic activities of L-PAF, including how it affects serotonin release from platelets, blood pressure in rats, and cytotoxic responses in normal and leukemic cells, are discussed in relation to its D-enantiomer, 3-alkyl-2-acetyl-GPC, and the 2-acetamide analog. The kinetic events of the cellular responses in both normal and HL-60 cells were characterized in relation to the antineoplastic activities of unnatural ether-linked phospholipid analogs that are structurally related to L-PAF.