THE SUPPRESSION OF FIBROBLAST GROWTH-FACTOR-2 FIBROBLAST GROWTH-FACTOR-4-DEPENDENT TUMOR ANGIOGENESIS AND GROWTH BY THE ANTI-GROWTH FACTOR ACTIVITY OF DEXTRAN DERIVATIVE (CMDB7)

Our previous studies showed that carboxymethyl benzylamide dextran (CM DB7) blocks basic fibroblast growth factor (FGF-2)-dependent cell prol iferation of a human breast epithelial line (HBL100), suggesting its p otential role as a potent antiangiogenic substance. The derived cell l ine (HH9), which was transformed with the hst/FGF4 gene, has been show n to be highly proliferative in vitro and to induce angiogenic tumours in nude mice. We show here that CMDB7 inhibits the mitogenic activiti es of the conditioned media from HBL 100 and HH9 cells in a dose-depen dent manner. When HH9 cells were injected s.c. into nude mice, CMDB7 t reatment (300 mg kg(-1) week(-1)) suppressed the tumour take and the t umour growth by about 50% and 80% respectively. Immunohistochemical an alysis showed a highly significant decrease, by more than threefold, i n the endothelial density of viable tumour regions, together with a si gnificant increase in the necrosis area. This antiangiogenic activity of CMDB7 was further demonstrated by direct inhibition of calf pulmona ry artery (CPAE) and human umbilical vein (HUVEC) endothelial cell pro liferation and migration in vitro. In addition, we showed that CMDB7 i nhibits specifically the mitogenic effects of the growth factors that bind to heparin such as FGF-2, FGF-4, platelet-derived growth factor ( PDGF-BB) and transforming growth factor (TGF-beta 1), but not those of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1). These results demonstrate that CMDB7 inhibits FGF-2/FGF-4-dependent t umour growth and angiogenesis, most likely by disrupting the autocrine and paracrine effects of growth factors released from the tumour cell s.