title: Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2.
abstract: More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. To begin to define the role COX-2 plays in driving bone cancer pain, we used an in vivo model where murine osteolytic 2472 sarcoma cells were injected and confined to the intramedullary space of the femur in male C3HHeJ mice. After tumor implantation, mice develop ongoing and movement-evoked bone cancer pain-related behaviors, extensive tumor-induced bone resorption, infiltration of the marrow space by tumor cells, and stereotypic neurochemical alterations in the spinal cord reflective of a persistent pain state. Thus, after injection of tumor cells, bone destruction is first evident at day 6, and pain-related behaviors are maximal at day 14. A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow [MF. tricyclic; 0.015%, p.o.] from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.
authors.affiliation: Neurosystems Center and Department of Preventive Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Mary Ann C
authors.initials: MA
authors.lastname: Sabino
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ghilardi
authors.forename: Joost L M
authors.initials: JL
authors.lastname: Jongen
authors.forename: Cathy P
authors.initials: CP
authors.lastname: Keyser
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Luger
authors.forename: David B
authors.initials: DB
authors.lastname: Mach
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Peters
authors.forename: Scott D
authors.initials: SD
authors.lastname: Rogers
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schwei
authors.forename: Carmen
authors.initials: C
authors.lastname: de Felipe
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D015576:Hyperostosis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D012516:Osteosarcoma / Q000150:complications* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D011451:Prostaglandin-Endoperoxide Synthases; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases