INHIBITION OF ANGIOGENESIS AND MURINE HEMANGIOMA GROWTH BY BATIMASTAT, A SYNTHETIC INHIBITOR OF MATRIX METALLOPROTEINASES

Background: The importance of matrix metalloproteinases in angiogenesi s, tumor growth, and metastasis is well known. However, little is know n about the role of matrix metalloproteinases in the formation of hema ngiomas and about the possible therapeutic use of matrix metalloprotei nase inhibitors in aggressive vascular tumors. Purpose: To study the r ole of matrix metalloproteinase in vascular tumors, we tested the anti neoplastic activity of a synthetic inhibitor of matrix metalloproteina ses, batimastat, on an experimental model of hemangioma, formed by mur ine endothelioma cells transformed by polyoma middle-T oncogene (eEnd. 1). Methods: The effect of batimastat was studied in vivo on the forma tion of hemorrhaging, cavernous hemangiomas by eEnd.1 endothelioma cel ls injected subcutaneously in nude mice and on the angiogenic response induced by an endothelioma cell supernatant embedded in a pellet of r econstituted basement membrane (Matrigel). The effect of batimastat wa s investigated in vitro on endothelial cell proliferation, motility, a nd invasion of a layer of Matrigel. Results: Daily treatment with bati mastat (30, 3, and 0.3 mg/kg at the site of eEnd.1 cell injection) inh ibited tumor growth, with increased doubling time. The carboxamide der ivative of batimastat, BB-374, a poor inhibitor of matrix metalloprote inase activity, was less active in reducing hemangioma growth. Histolo gic analysis of treated tumors indicated a reduction in the size of bl ood-filled spaces and in hemorrhage. Batimastat also inhibited the ang iogenic response induced by cultured eEnd.1 endothelioma cell supernat ant embedded in a pellet of Matrigel. Batimastat significantly inhibit ed endothelial cell invasion in vitro through a layer of Matrigel, but it showed no direct cytotoxic activity. Conclusions: Batimastat reduc es in vivo growth of experimental hemangiomas, most probably by blocki ng endothelial cell recruitment by the transformed cells or by interfe ring with cell organization in vascular structures. Implications: Thes e results confirm the importance of matrix metalloproteinase in endoth elial cell recruitment that occurs in angiogenesis and in the formatio n of vascular tumors and suggest a therapeutic potential for synthetic matrix metalloproteinase inhibitors.