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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Evaluation of Original Dual Thromboxane A₂ Modulators as Antiangiogenic Agents

Natural and Synthetic Drugs Research Centre, Laboratory of Medicinal Chemistry (X.d.L., J.-M.D., B.P.), Metastasis Research Laboratory, Center for Experimental Cancer Research (T.D., D.W., A.B., V.C.), and Cellular and Molecular Therapeutic Center (V.B.), University of Liège, Liège, Belgium

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A₂ (TXA₂) inhibitors derived from torasemide, a marketed loop diuretic with TXA₂ antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA₂ receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA₂ receptor agonist, and inhibited platelet TXA₂ synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA₂ inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor (VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 µM. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca²⁺ pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA₂ pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F₂) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl]urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2-p-toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA₂ inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration.

Address correspondence to: Dr. Xavier de Leval, Natural and Synthetic Drugs Research Center, Laboratory of Medicinal Chemistry, University of Liège, Avenue de l'hôpital, Bat. B36, B-4000 Liège, Belgium. E-mail: xdeleval{at}ulg.ac.be