title: Cyclooxygenase-1 is overexpressed and promotes angiogenic growth factor production in ovarian cancer.
abstract: Inhibition of cyclooygenase-2 (COX-2) catalytic activity has proven successful in restricting the growth of epithelial-derived cancers in vivo. Whether COX-2 inhibitor therapy would be beneficial in the prevention and/or treatment of ovarian cancer, the most lethal gynecological malignancy worldwide, is not known. Most patients with ovarian cancer undergo cytoreductive therapy. Because many of the cytotoxic drugs used to treat ovarian cancer induce COX-2 expression, samples from patients that had not undergone cytoreductive therapy were specifically chosen for COX isoform expression analysis. A majority of specimens exhibited elevated levels of COX-1, not COX-2, mRNA, and protein compared with normal ovarian tissue. Focal regions within the tumor expressing high COX-1 also had elevated levels of pro-angiogenic proteins. Selective inhibition of COX-1, not COX-2, inhibited arachidonic acid-stimulated vascular endothelial growth factor production, which could be reversed by cotreatment with prostaglandin E(2). Thus, COX-1 may contribute to carcinoma development in the ovary through stimulation of neovascularization. Clinical studies testing the efficacy of COX inhibition as adjuvant therapy for ovarian cancer may see more beneficial effects with adjuvant therapy with either a COX-1 selective or nonselective cyclooxygenase inhibitor as compared with a COX-2 selective drug.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Rajnish A
authors.initials: RA
authors.lastname: Gupta
authors.forename: Lovella V
authors.initials: LV
authors.lastname: Tejada
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Tong
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Das
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Sudhansu K
authors.initials: SK
authors.lastname: Dey
authors.forename: Raymond N
authors.initials: RN
authors.lastname: DuBois
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D015152:Blotting, Northern; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis*; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone