Despite advances in diagnosis and treatment, cancer continues to pose major clinical challenges and is the focus of efforts to develop therapies that combine effectiveness with low toxicity. Among these, angiogenesis is a current target of attempts aimed to reduce tumor vascularization and growth (1, 2), because it holds a promise for more effective and better tolerated approaches for cancer treatment. The peroxisomal proliferator-activated nuclear receptors (PPARs), 2 i.e. PPAR␣, PPAR␥, and PPAR␦, control the transcription of genes mostly involved in the regulation of lipid metabolism and energy homeostasis. Although several roles for the PPAR␦ and -␥ isotypes in the pathophysiology of cancer have been proposed (3-5), recent animal studies have identified PPAR␣ ligands as effective inhibitors of tumor angiogenesis and growth (6 -8).The potential significance of these findings has been emphasized by epidemiological data (9 -12), and by studies in human cancer cell lines (13-16), suggesting that PPAR␣ ligands such as Fenofibrate and Bezafibrate may have beneficial effects in the prognosis of human cancer. A unique feature of these PPAR␣ ligands is that, through their long history of clinical use as hypolipidemic drugs, they have been shown to be well tolerated and to have limited side effects and/or toxicity, indicating that they could serve as targets for the development of novel, safer, and with low toxicity anti-cancer treatments.The PPAR␣-mediated transcriptional regulation of members of the CYP2C gene subfamily of cytochrome P450s is well established (17, 18), as is the role of these enzymes in the metabolism and bio-activation of arachidonic acid (AA) (19). The CYP2C epoxygenases metabolize AA to 5,8,11,and 14,, and these metabolites have been characterized as pro-angiogenic lipids in vitro (20 -22) and in vivo (23). The demonstration that the anti-tumorigenic effects of PPAR␣ ligand activation were associated with reductions in the endothelial expression of the murine Cyp2c44 epoxygenase and in the levels of plasma and endothelial EETs (6), suggested pro-angiogenic and pro-tumorigenic roles for this epoxygenase, and pointed to this enzyme as a target of the anti-tumorigenic effects resulting from PPAR␣ activation (6). The murine Cyp2c44 epoxygenase generates 11,12-and 14,15-EET as its major products (24), is expressed in endothelial cells (6), and is under PPAR␣ transcriptional control (6). Similarly, human CYP2C8 and CYP2C9, catalytic homologues of murine Cyp2c44 (25), have been identified as endothelial epoxygenases (21,22), and their participation in