TAXOL PROVIDES A 2ND SIGNAL FOR MURINE MACROPHAGE TUMORICIDAL ACTIVITY

The anticancer drug, taxol, blocks cell division by stabilizing microt ubules. However, taxol has distinct cell-cycle-independent effects. Fo r example, taxol and bacterial LPS induce strikingly similar responses in murine macrophages. Here we report that taxol, like LPS, provides a ''second'' signal for murine macrophage activation to tumoricidal ac tivity. Tumoricidal activity was determined by the release of Cr-51 fr om prelabeled P815 mastocytoma target cells. Taxol or LPS alone weakly induced C3H/Ouj (Lps(n)) murine macrophages to kill P815 mastocytoma cells, and tumoricidal activity was not induced by the classic ''primi ng'' signal, IFN-gamma. However, combinations of taxol or LPS with IFN -gamma synergized to activate macrophages to lyse tumor cells. Taxol a ctivation of macrophages required an intact LPS signaling pathway, as taxol did not induce IFN-gamma-treated C3H/Hej (Lps(d)) macrophages to lyse target cells. In normal (Lps(n)) murine macrophages, IFN-gamma, LPS, or taxol alone induced low or moderate levels of nitric oxide syn thase gene expression and nitric oxide secretion. However, this gene a nd cytostatic metabolite were induced synergistically by combinations of taxol or LPS with IFN-gamma. Secretion of nitric oxide correlated w ith tumor cell killing, and taxol-activated macrophages failed to kill tumor targets in the presence of N(G)-monomethyl-L-arginine, a compet itive inhibitor of nitric oxide synthase. The data illustrate the pote ntial for taxol to activate macrophage mediated-antitumor mechanisms i n addition to its better characterized role as an anti-mitotic agent.