MODULATION OF ANTITUMOR-ACTIVITY OF MACROPHAGES BY REGULATION OF EICOSANOIDS AND CYTOKINE PRODUCTION

Production and release of arachidonic acid (AA) compounds (eicosanoids: prostaglandinscycloxygenase and leukotrienes-lipoxygenase) and monokines (TNF-alpha, IL-1 and others) play an essential role in the expression of antitumour activity of macrophages (MO). We investigated the possibility of inducing the antitumour activity of peritoneal murine and human MO by regulating their production of eicosanoids and monokines. The antitumour activity of MO was inversely correlated to production of PGE(2) and directly correlated to production of leukotrienes (LTC(4) and LTD(4). Thus, indomethacin rendered murine MO cytostatic against tumour cells and enhanced the antitumour activity of human peritoneal macrophages from renal patients on CAPD (continuous ambulatory peritoneal dialysis), and leukotriene inhibitors (NDGA-nordihydroguaiaretic acid and AA861) prevented antitumour cytostatic activity of MO. Human peritoneal MO collected during periods of inflammation (infectious peritonitis) were more active against tumour cells, especially when cultured in the presence of LPS, and their activity was correlated to increase with the release of TNF and of IL-1 beta. Human peritoneal MO from inflammation-free patients reacted against a human tumour cell line if cultured with LPS and TPA phorbol-myristate acetate) and were therapeutically effective against the same palpable s.c. tumours implanted in nude mice.