Low-molecular-weight dextran derivatives (f-CMDB) enter the nucleus and are better cell-growth inhibitors compared with parent CMDB polymers

Carboxymethyldextrans-benzylamide (CMDB) are dextran derivatives that are s tatistically substituted with carboxymethyl and benzylamide groups. These m olecules display a variety of biological effects, one of which is their inh ibitory activity against mammary tumor cell growth, both in vitro and in vi vo. We and others have previously shown that the effects of CMDB on cell gr owth are related to their ability to interact with the growth factor FGF-2. The binding modifies the conformation of FGF-2, leading to the suppression of its mitogenic activity. Here, the method previously reported to fragmen t natural polysaccharide fucans has been applied to CMDB (80,000 g/mol). f- CMDB (fragmented CMDB) of molecular weights from 6000 to 20,000 g/mol were found to be more potent inhibitors of MCF7 mammary tumor cell growth than h igh-molecular-weight CMDB. Confocal microscopy experiments using CMDB and f -CMDB labeled with the fluorophore DTAF (5-([4,6-dichlorotriazine-2-yl]amin o) fluorescein) indicate that only low-molecular-weight f-CMDB penetrate in to the nucleus of MCF7 cells. It is thus assumed that the better inhibitory properties demonstrated by f-CMDB, compared with CMDB, are related to thei r better ability to penetrate the nucleus and interact with nuclear targets , including topoisomerase II. The DNA relaxation properties of the latter a re inhibited in vitro by both CMDB and f-CMDB. These findings could help us to develop models of low-molecular-weight oligosaccharide derivatives exhi biting better antiproliferative and antitumor properties. (C) 1999 Elsevier Science Ltd. All rights reserved.