title: Prevalence of 5-lipoxygenase expression in canine osteosarcoma and the effects of a dual 5-lipoxygenase/cyclooxygenase inhibitor on osteosarcoma cells in vitro and in vivo.
abstract: Canine osteosarcoma is an insidious disease with few effective treatment modalities; therefore, use of pharmacologic intervention to improve mortality or morbidity is constantly sought. The use of cyclooxygenase enzyme inhibitors has been an area of interest with limited efficacy based on retrospective examination of tumor expression and in vivo cell proliferation models. Recently, examination of dual cyclooxygenase and 5-lipoxygenase inhibitors in human and canine oncology suggests that 5-lipoxygenase inhibitors may be an effective approach in vitro and during tumor induction in rodent models. Therefore, the authors decided to examine 5-lipoxygenase expression in primary canine osteosarcoma samples and have shown that approximately 65% of osteosarcomas label positive for cytoplasmic 5-lipoxygenase. Further examination of a cell culture and xenograft model shows similar 5-lipoxygenase expression. Surprisingly, a canine 5-lipoxygenase inhibitor (tepoxalin) significantly reduced cell proliferation at physiologic doses in vitro and diminished xenograft tumor growth in nude mice, suggesting that further investigation is needed. Traditionally, 5-lipoxygense leads to production of lipid mediators, such as leukotriene B(4) and 5-oxo-eicosatetraenoic acid, which, when added back to the media of tepoxalin-treated cells, did not recover cell proliferation. The lack of nuclear staining in primary and xenografted tumors and the lack of response to eicoasanoids suggest that lipid mediator production is not the primary means by which tepoxalin acts to alter proliferation. Regardless of the mechanisms involved in retarding cell proliferation, future investigation is warranted.
authors.affiliation: Department of Clinical Sciences, Cornell University College of Veterinary Medicine, VMC 1-120, Box 34, Ithaca, NY 14853, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Goupil
authors.forename: J J
authors.initials: JJ
authors.lastname: Bushey
authors.forename: J
authors.initials: J
authors.lastname: Peters-Kennedy
authors.forename: J J
authors.initials: JJ
authors.lastname: Wakshlag
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000662:veterinary*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004283:Dog Diseases / Q000188:drug therapy / Q000201:enzymology*; D004285:Dogs; D005260:Female; D007150:Immunohistochemistry / Q000662:veterinary; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000662:veterinary*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000662:veterinary
chemical_list: D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D001094:Arachidonate 5-Lipoxygenase; C073135:tepoxalin