Selective anti-endothelial effects of protracted low-dose BAL-9504, a novel geranylgeranyl-transferase inhibitor

Because the anti-endothelial effects of agents such as interferon alpha, endostatin, and various chemotherapeutic drugs appear to be optimal after protracted, frequent dosing, both in vitro and in vivo, using low concentrations/doses of drugs, we tested the geranylgeranyl transferase inhibitor BAL-9504 ((E,E,E) [2-oxo-2-[[(3,7,11,15-tetramethyl-2,6,10,14 hexadecatetraenyl)-oxy]amino]ethyl] phospbonic acid) in this manner on different human cell types, including endothelial, breast cancer cells and fibroblasts. We found that human endothelial cells were preferentially affected with respect to inhibition of proliferation, induction of apoptosis, suppression of adhesion to fibronectin, and blockade of cell migration, by daily exposure to low concentrations of BAL-9504 for 6 days. These results may have implications in terms of both increasing anti-tumor efficacy, mediated by antiangiogenic mechanisms, and reducing toxic side effects. (C) 2003 Elsevier B.V. All rights reserved.