Cytotoxicity of platelet activating factor and related alkyl- phospholipid
analogs in human leukemia cells, polymorphonuclear neutrophils, and skin
fibroblasts
DR Hoffman, J Hajdu and F Snyder
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.
Volume 63,
Issue 3,
pp. 545-552,
03/01/1984
Copyright © 1984 by The American Society of Hematology
