SUPEROXIDE PRODUCTION BY MACROPHAGES STIMULATED IN-VIVO WITH SYNTHETIC ETHER LIPIDS

The anticancer activity of synthetic ether Lipids may depend in part u pon their ability to activate cells of the monocyte/macrophage lineage . In the present study, we have sought to determine whether -octadecyl -2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OMe) and related ether lipids enhance superoxide production by mouse peritoneal macrophages. Ether lipids were administered intraperitoneally to C57BL/6 mice 4 d after injection with thioglycollate broth. Elicited peritoneal macroph ages were harvested and purified one day later, and superoxide product ion was detected by measuring the superoxide dismutase inhibitable red uction of cytochrome c. Low levels of superoxide were secreted by macr ophages in the absence of phorbol 12-myristate 13-acetate (PMA). When PMA was added in vitro to macrophages from ET-18-OMe-treated mice, the se cells secreted 194.2 nmol superoxide/mg protein in comparison to 53 .5 nmol superoxide/mg protein for PMA-treated control cells. The in vi tro treatment of the macrophages with ET-18-OMe was not effective in s timulating superoxide secretion. Macrophages harvested from mice treat ed with a series of ether lipids (with and without phosphorus) were ex amined, and superoxide secretion was found to vary with structure. AM- 18-OEt and CP-7 were the most effective compounds, secreting 8.6 and 1 1.9 times more superoxide, respectively, than PMA-stimulated control c ells. Moreover, direct cytotoxicity of the compounds for HL60 human pr omyelocytic leukemic cells did not necessarily correlate with the abil ity of each drug to increase macrophage superoxide production.