THE SULFONIC-ACID POLYMERS PAMPS [POLY(2-ACRYLAMIDO-2-METHYL-1-PROPANESULFONIC ACID)] AND RELATED ANALOGS ARE HIGHLY POTENT INHIBITORS OF ANGIOGENESIS

The sulfonic acid polymers poly(2-acrylamido-2-methyl-1-propanesulfoni c acid) (PAMPS), poly(4-styrenesulfonic acid) (PSS), and poly(anethole sulfonic acid) (PAS) proved to be highly potent inhibitors of angiogen esis in the chick chorioallantoic membrane (CAM) assay. PAMPS was foun d to achieve a dose-dependent inhibition of microvessel formation in t he CAM assay ranging from 57 +/- 16% inhibition at 10 mu g/disc to 72 +/- 15% at 150 mu g/disc. Also, PSS and PAS caused a strong inhibition of angiogenesis (55 +/- 19% and 48 +/- 16%, respectively, at 50 mu g/ disc), whereas poly(vinylsulfonic acid) (PVS) was found to be inactive at this dose. The compounds proved to be nontoxic for the developing chick embryo at these doses. Suramin, which was included as a referenc e compound, caused only a slight inhibition of vascular density, at a dose of 150 mu g/disc, whereas pentosan polysulfate (PPS) was found to be toxic. PAMPS, PAS, and PSS, but not PVS, inhibited microvessel for mation in the rat aorta-ring assay. In addition, the increased [H-3-me thyl]dThd uptake in endothelial cells in vitro upon stimulation with b asic fibroblast growth factor (bFGF) was inhibited by PAMPS, PAS, and PSS at 20 mu g/ml. A strong correlation (r = 0.95) was found between t he antiangiogenic effect of the sulfonic acid polymers in the CAM assa y and their inhibition of the bFGF-induced mitogenic response, indicat ing that bFGF is the target for these sulfonic acid polymers. These re sults suggest that sulfonic acid polymers, and in particular PAMPS, ma y be considered as specific, nontoxic angiogenesis inhibitors.