ANTIPROLIFERATIVE CAPACITY OF SYNTHETIC DEXTRANS ON SMOOTH-MUSCLE CELL-GROWTH - THE MODEL OF DERIVATIZED DEXTRANS AS HEPARIN-LIKE POLYMERS

Proliferation of vascular smooth muscle cells (SMC) is postulated to b e a key step in the pathogenesis of atherosclerosis or restenosis afte r vascular interventions such as angioplasty. Natural glycosaminoglyca ns, such as heparin and heparan sulfate, are known for their ability t o inhibit SMC proliferation in vivo and in vitro. The antiproliferativ e activity of synthetic derivatized dextrans exhibiting heparin-like a nticoagulant and anticomplement capacities have been investigated with rat aorta smooth muscle cells in culture. We report here that some de rivatized dextrans grafted with benzylamide sulfonate moieties are pot ent antiproliferative agents for rat smooth muscle cell (SMC) in vitro . These synthetic polymers inhibit the SMC proliferation as well as he parin. The SMC growth inhibition is dose dependent, reversible and non -toxic. Highly anionic carboxylic dextrans are not capable of inhibiti ng the SMC growth, excluding a simple charge effect mechanism. Using f luorescent (DTAF) probes, we demonstrated that the synthetic antiproli ferative polymers and heparin are internalized into the SMC. No bindin g or internalization was observed with native dextran devoid of antipr oliferative capacity. We conclude that a suitable distribution of func tional groups on the dextran backbone can simulate heparin activity in terms of antiproliferative capacity on SMC growth.