INHIBITION OF FIBROBLAST AND SMOOTH-MUSCLE CELL-PROLIFERATION AND MIGRATION INVITRO BY A NOVEL AMINOCHROMONE U-67154

Medial smooth muscle cell migration and neointimal proliferation are primary contributors to the delayed restenosis that occurs after percutaneous transluminal coronary angioplasty. In this study, we describe the antiproliferative and antichemotactic properties of U-67154, the parent compound of a series of novel aminochromones, determined using in vitro fibroblast and smooth muscle cell culture systems. U-67154 inhibited the induction of DNA synthesis in confluent BALB/c 3T3 fibroblasts and early-passage rat aortic smooth muscle cells by several different growth factors in a concentration-dependent manner. U-67154 similarly inhibited the proliferation of these cells stimulated by serum. Growth-factor-induced chemotaxis of fibroblasts and early-passage rat aortic smooth muscle cells also was inhibited by U-67154 in a concentration-dependent manner. The IC50S for all of these functions were similar (between 120 and 200 muM). Such antiproliferative and antichemotactic effects did not result from cytotoxicity (as measured by lactate dehydrogenase release, neutral red uptake or nonspecific inhibition of protein synthesis). Most important, inhibition of long-term proliferation of fibroblasts and early-passage smooth muscle cells by U-67154 was fully reversible upon removal of the drug. Thus, U-67154 represents a class of novel, noncytotoxic compounds that may prove useful in the treatment of proliferative disorders such as delayed restenosis after percutaneous transluminal coronary angioplasty.