title: Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy.
abstract: Angiogenesis is required for multistage carcinogenesis. The inducible enzyme cyclooxygenase-2 (COX-2) is an important mediator of angiogenesis and tumor growth. COX-2 expression occurs in a wide range of preneoplastic and malignant conditions; and the enzyme has been localized to the neoplastic cells, endothelial cells, immune cells, and stromal fibroblasts within tumors. The proangiogenic effects of COX-2 are mediated primarily by three products of arachidonic metabolism: thromboxane A(2) (TXA(2)), prostaglandin E(2) (PGE(2)), and prostaglandin I(2) (PGI(2)). Downstream proangiogenic actions of these eicosanoid products include: (1) production of vascular endothelial growth factor; (2) promotion of vascular sprouting, migration, and tube formation; (3) enhanced endothelial cell survival via Bcl-2 expression and Akt signaling; (4) induction of matrix metalloproteinases; (5) activation of epidermal growth factor receptor-mediated angiogenesis; and (6) suppression of interleukin-12 production. Selective inhibition of COX-2 activity has been shown to suppress angiogenesis in vitro and in vivo. Because these agents are safe and well tolerated, selective COX-2 inhibitors could have clinical utility as antiangiogenic agents for cancer prevention, as well as for intervention in established disease alone or in combination with chemotherapy, radiation, and biological therapies.
authors.affiliation: Department of Translational Medicine, NeoPharm Inc., 150 Field Drive, Suite 195, Lake Forest, IL 60045, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gately
authors.forename: William W
authors.initials: WW
authors.lastname: Li
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000068579:Celecoxib; D002465:Cell Movement; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology*; D007783:Lactones / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011720:Pyrazoles; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones; D013928:Thromboxane A2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; C116926:rofecoxib; D018664:Interleukin-12; D013928:Thromboxane A2; D004815:Epidermal Growth Factor; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases; D000068579:Celecoxib; D015232:Dinoprostone