Correlation between immune and vascular activities of xanthenone acetic acid antitumor agents

To determine whether xanthenone acetic acid (XAA) analogues of flavone acetic acid (FAA) have similar ischemic and nonischemic mechanisms of antitumor action to FAA, a series of such compounds was evaluated in vivo and in vitro. Necrotising activity and changes in tumor blood flow were measured in Colon 38 tumors, and morphological changes assessed in immune cell-infiltrated EMT6 tumor cell spheroids, after treatment with FAA, XAA and its derivatives (5-methyl XAA, 5,6-dimethyl XAA, 3-O-methyl XAA, 8-methyl XAA and xanthenone-4,5-diacetic acid). FAA, XAA and the 5-methyl and 5,6-dimethyl analogues of XAA were active in inducing tumor necrosis, falls in tumor perfusion and characteristic morphological changes in multicellular spheroids. The other XAA analogues lacked these activities. 5-methyl XAA and 5,6-dimethyl XAA were more potent than FAA or XAA. The results suggest that XAA and its analogues have the same mechanisms of action as FAA, and that both the vascular and the immune effects of these compounds are mediated via a common biochemical receptor.