INHIBITION OF MCF-7RAS TUMOR-GROWTH BY CARBOXYMETHYL BENZYLAMIDE DEXTRAN - BLOCKAGE OF THE PARACRINE EFFECT AND RECEPTOR-BINDING OF TRANSFORMING-GROWTH-FACTOR BETA-1 AND PLATELET-DERIVED GROWTH FACTOR-BB

The highly tumorigenic human breast cancer MCF-7ras line (Ha-ras-trans fected MCF-7 cell line) loses estrogen dependence and secretes diffusi ble growth factors that support its own tumor growth in vivo. Our prev ious studies showed that carboxymethyl benzylamide dextran (CMDB7) inh ibits the growth of breast MCF-7 and MCF-7ras cell lines. In this stud y, we have shown that conditioned medium (CM) from MCF-7 and MCF-7ras cells stimulated the DNA synthesis of BALB/c3T3 fibroblasts and that C MDB7 strongly inhibited these mitogenic effects in a dose-dependent ma nner. Neutralizing antibodies against platelet-derived growth factor ( PDGF) partially inhibited the mitogenic effect of MCF-7ras CM, The flo w cytometry analysis of the cell cycle showed that the CM of tumor cel ls increased the percentage of fibroblasts in S phase and that CMDB7 b locked them in G(0)/G(1) phase. CMDB7 inhibited the mitogenic effect o f PDGF-BB and transforming growth factor (TGF) beta 1 but not those of epidermal growth factors and insulin-like growth factor on BALB/c3T3 fibroblasts. CMDB7 increased the electrophoretic mobility of radiolabe led PDGF-BB and TGF-beta 1, apparently by forming a stable complex wit h these factors. On intact BALB/c3T3 fibroblasts, binding of iodinated growth factors (I-125-TGF-beta 1 and I-125-PDGF) to their receptors w as completely displaced by CMDB7. In vivo studies demonstrated that s. c. injection of CMDB7 inhibited by 66% the tumor growth of MCF-7ras xe nografts in nude mice. These results showed that CMDB7 inhibits the mi togenic effect of growth factors released from MCF-7 and MCF-7ras cell s and suppresses tumor growth in the MCF-7ras model.