Anti-proliferative and antitumoral activities of a functionalized dextran (CMDBJ) on the 1205 L-U human tumor melanoma cells.

Carboxy methyl dextran benzylamide jorge (CMDBJ) is a derivatized dextran prepared from native dextran after random carboxymethylation of hydroxyl groups on D-glucose units (CM) and consecutive conversion of some carboxylate groups to benzylamide structures (B). This polymer exhibits an inhibitory action upon the proliferation of 1205 L-U human melanoma cells. At low concentrations, this compound exerts a cytostatic effect whereas, at higher concentrations, a cytotoxicity appears within 24 hours of treatment. The 1205 L-U cell line forms subcutaneous angiogenic tumors in athymic mice and, after several weeks, spontaneously forms micrometastasis in the lungs. We demonstrated that the CMDBJ treatment of animals not only reduces the rapid growth of primary tumors but also induces tumor regression and tumor necrosis. Moreover, CMDBJ treatment blocks the appearance of lung metastasis. Pleiotrophin (PTN), heparin-binding angiogenic growth factor, is secreted by 1205 L-U cells and breast tumor MDA-MB 231 cells. CMDBJ, as an inhibitor of heparin-binding growth factor activities, suppresses the mitogenic activity of conditioned media from 1205 L-U and MDA-MB 231 on endothelial HUVEC cells. We conclude that CMDBJ can inhibit the in vitro cell proliferation of 1205 L-U cells and 1205 L-U tumor development in athymic mice and that PTN secreted by these cells could be involved in this inhibition.

Interaction of specifically chemically modified dextrans with transforming growth factor beta1: potentiation of its biological activity.

Transforming growth factor beta (TGFbeta), a potent multifunctional cytokine, is well known to demonstrate heparin binding ability. This study investigated the binding capacity of heparin-like family of chemically modified dextrans to TGFbeta1. Dextran derivatives with various substitution contents in carboxymethyl, benzylamide and sulfate groups were evaluated using a gel mobility shift assay. This structure-function study indicated that a synergistic role of benzylamide and sulfate substituents resulted in an optimal interaction with the growth factor. The effect of these polymers on the biological response of TGFbeta1 was assessed using mink lung epithelial cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct (PAI/Luc). When the growth factor was mixed with 250 microg/mL of carboxymethyl-benzylamide-dextran (DCMB) or carboxymethyl-benzylamide-sulfate-dextran (DCMBSu), the luciferase gene expression was enhanced. Only polymers exhibiting TGFbeta1 binding demonstrated a biological potentiating effect. However, this effect was strongly amplified as the cell plating time increased (35-fold increase with a 2 days plating time versus 1.1-fold increase with a 4 hr plating time at a 0.25 ng/mL concentration of TGFbeta1). TGFbeta1 induced the PAI/Luc construct in a dose-dependent fashion but its effect diminished when added to cells previously cultured for 24 and 48 hr. The results indicated that the potentiating effect required a complex formation between TGFbeta1 and polymers, the action of which seeming to locally maintain TGFbeta1 in an active form. TGFbeta isoforms playing a key role in the process of bone repair, specifically designed functionalized dextrans could potentiate the in vivo TGFbeta1 biological effect and be used in the field of wound healing applications.