Stimulation of macrophage tumouricidal activity by 5,6-dimethyl-xanthenone-4-acetic acid, a potent analogue of the antitumour agent flavone-8-acetic acid.

The new antitumour drug 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA; NSC 640488) was 14-fold more potent than the investigational chemotherapeutic drug flavone-8-acetic acid (NSC 347512) in stimulating tumouricidal activity in cultures of resident murine peritoneal macrophages. The tumouricidal activity of thioglycollate-elicited and Bacillus Calmette-Guérin-primed macrophages was also significantly enhanced by 5,6-MeXAA. Stimulation of macrophage tumouricidal activity by 5,6-MeXAA was not affected by inhibitors of superoxide and nitric oxide production, but was reduced by cyclosporin A, an inhibitor of protein secretion. Inhibitors of neutral proteases had no effect. Cortisone, dexamethasone, indomethacin, dibutyryl cAMP, prostaglandin E2 and prostacyclin, but not prostaglandin F2 alpha, inhibited stimulation, suggesting the involvement of tumour necrosis factor-alpha (TNF). However, antibodies to TNF did not inhibit stimulation. The results suggest that 5,6-MeXAA acts on macrophages in a manner similar to that of endotoxin, utilizing a pathway which includes arachidonic acid metabolism and requiring cell-cell contact with target cells for a tumouricidal effect.