EFFECTS OF AMINO AND IMINO ACRIDINES ON TUMOR-NECROSIS-FACTOR PRODUCTION BY HUMAN-LEUKOCYTES

Tumor necrosis factor (TNF) is a multifunctional cytokine with diverse effects on different cells and tissues. The biological activity of TN F is described on the basis of its cytotoxic action in vivo and in vit ro. Different acridines were systematically synthesized and their effe cts were tested on endotoxin and Staphylococcus aureus - induced TNF p roduction by human leukocytes. 9-aminobutylacridine and 9-ethylaminoac ridine totally abrogated the TNF production of leucocytes at a concent ration of 3.5 mu M, whereas 9-imino-10-butylacridine and 9-imino-10-et hylacridine exerted only a 50% inhibition in the same concentration. D erivatives designated as 9-amino-(2-dimethylamino-ethyl)-acridine and 9-imino-10-(2-dimethylamino-ethyl)-acridine in a concentration of 7 mu M exerted only a 30% and a 10% inhibition respectively. A significant modulation of TNF production was not observed when other alkylated de rivatives in this series were applied. The TNF-mediated cytotoxic effe ct of monocytes against WEHI cells was also reduced by the most effect ive compounds. The acridines did not interfere with the expression of CD 14 molecules on monocytes. The exact mechanism of the suppression o f TNF synthesis by acridines remains to be elucidated, but might be us eful in the screening and evaluation of their anticancer properties an d antimalarial effects.