Cytotoxicity of platelet activating factor and related alkyl-phospholipid analogs in human leukemia cells, polymorphonuclear neutrophils, and skin fibroblasts.
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 greater than 1-alkyl-2-methoxy-GPC greater than D-PAF greater than 1-acyl-2-lyso-GPC greater than 1-alkyl-2-lyso-GPC greater than L-PAF. A time-sequenced progression of events caused by the most potent cytotoxic alkyl-phospholipid analogs was characterized by (a) a rapid decrease in the cellular uptake and incorporation of 3H-thymidine into DNA that was detectable 4 hr after exposure to the analog, (b) a release of lactate dehydrogenase activity into the media at 8 hr after exposure, and (c) a decrease in cell number due to cell death that begins at 12 hr after exposure. Treatment of HL-60 cells with 1-alkyl-2-methoxy-GPC for 1 hr destroyed 40% of the cells after a subsequent 24-hr 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. This report characterizes the kinetic events of the cellular responses in both normal and HL-60 cells in relation to the antineoplastic activities of unnatural ether-linked phospholipid analogs that are structurally related to L-PAF.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010972:Platelet Activating Factor / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D012867:Skin / Q000166:cytology
D000970:Antineoplastic Agents; C029271:O-deacetyl platelet activating factor; D010972:Platelet Activating Factor; D012710:Serum Albumin, Bovine; C026613:1-0-octadecyl 2-0-acetyl sn-glycero-3-phosphorylcholine; D007770:L-Lactate Dehydrogenase