SOLUTION STRUCTURE OF ACIDIC FIBROBLAST-GROWTH-FACTOR BOUND TO 1,3,6-NAPHTHALENETRISULFONATE - A MINIMAL MODEL FOR THE ANTI-TUMORAL ACTION OF SURAMINS AND SURADISTAS

Recent data show that anti-angiogenesis may provide a promising route to treat cancer. Fibroblast growth factors (FGFs) are powerful angioge nic polypeptides, whose mitogenic activity requires the presence of he parin-like compounds. It has been shown that angiogenesis promoted by FGFs on inhibition by monoclonal antibodies and antisense targeting ca n also inhibit tumour growth. Derivatives of suramin, a polysulfonated binaphthyl urea and binaphthylsulfonated derivatives of distamycin, s uradistas, constitute an important group of potential anti-cancer agen ts. These compounds compete with heparin in forming tight complexes wi th FGFs. This inhibits the recognition of these growth factors by thei r tyrosine kinase membrane receptors thereby suppressing their angioge nic activity. Here we show that 1,3,6-naphthalenetrisulfonate, a commo n chemical function of the suramins and suradistas with the highest an tiangiogenic activity inhibits the mitogenic activity of acidic fibrob last growth factor, and that this inhibition is relieved by increasing concentrations of heparin in the assay. We have also solved the three -dimensional structure in solution of the protein complexed to this co mpound. The structural data provide clues that may help in understandi ng the inhibitory effect of suramins and suradistas, and could contrib ute to the development of new anti-tumoral drugs. (C) 1998 Academic Pr ess.