A DIAMINOANTHRAQUINONE INHIBITOR OF ANGIOGENESIS

Tumor growth is dependent upon angiogenesis. There is an intense searc h for pharmacological inhibitors of angiogenesis as a novel approach t o treat angiogenic diseases, e.g., arthritis, diabetic retinopathy or cancer. A series of compounds, originally studied as potential protein kinase C inhibitors, included the diaminoanthraquinone NSC 639366 ami no)-2-hydroxypropyl]amino]-4-[(2,3-epoxypropyl) amino]-9,10-anthracene dione fumaric acid salt} (SPC-100097), was found to reversibly inhibit bovine endothelial cell growth with an IC50 that ranged between 1 and 4 nM. NSC 639366 reversibly inhibited endothelial cell migration, par ticularly endothelial cells stimulated by the potent angiogenic molecu le, basic fibroblast growth factor. The activity of secreted urokinase -type plasminogen activator and active interstitial collagenase, but n ot gelatinase, was inhibited by NSC 639366. In vivo, angiogenesis was significantly inhibited by NSC 639366 by using the chick chorioallanto ic membrane or the rat corneal bioassay. Two analogs of NSC 639366 did not inhibit endothelial cell growth. These experiments introduce a no vel compound that could be clinically useful against angiogenic diseas es and encourage further development of compounds that inhibit the pla sminogen-plasmin system known to be a key regulator of angiogenesis.