title: Microsomal prostaglandin E synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice.
abstract: OBJECTIVE
  Nonsteroidal anti-inflammatory drugs are a therapeutic modality for chronic cancer pain arising from bone metastases. Chronic administration of a cyclooxygenase (COX)-2 inhibitor is effective to bone cancer-related pain. However, adverse cardiovascular effects have limited COX-2 inhibitor therapy, and elucidation of better targets for blocking prostaglandin (PG) biosynthesis is necessary. Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that catalyzes isomerization of the endoperoxide PGH(2) to PGE(2). To investigate the validity of mPGES-1 as a therapeutic target, we evaluated bone cancer pain-related behaviors in mPGES-1 knockout (PGES-1-/-) mice.
  
  
  METHODS
  Lewis lung carcinoma cells (LLCCs) were injected into the intramedullary space of the femur of wild-type (WT) and PGES-1-/- mice. Pain-related behaviors were evaluated.
  
  
  RESULTS
  PGES-1-/- mice exhibited reduced tumor growth in bone marrow compared to WT. The expression of pro-calcitonin gene-related peptide (CGPR) in the dorsal root ganglia of L(1-5) was significantly higher in WT mice at day 14, whereas it was unchanged in mPGES-1 mice. In the observation of pain-related behaviors, mPGES-1-/- mice exhibited significantly fewer spontaneous flinches and their onset was several days later than WT. The appearance of other pain-related behaviors in mPGES-1-/- mice was also delayed as compared to WT. LLCC-injected WT mice treated with a COX-2 inhibitor, celecoxib, exhibited similar temporal changes to mPGES1-/-.
  
  
  CONCLUSIONS
  The present results suggest that mPGES-1 plays a crucial role in the enhancement of bone cancer growth and bone cancer pain, and that inhibition of mPGES-1 may have clinical utility in the management of bone cancer pain.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Isono
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kanako
authors.initials: K
authors.lastname: Hosono
authors.forename: Izumi
authors.initials: I
authors.lastname: Hayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakagami
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Yves A
authors.initials: YA
authors.lastname: DeClerck
authors.forename: Hirotugu
authors.initials: H
authors.lastname: Okamoto
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001859:Bone Neoplasms / Q000150:complications / Q000473:pathology* / Q000556:secondary; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016503:Drug Delivery Systems; D005727:Ganglia, Spinal / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D000068579:Celecoxib; D015740:Calcitonin Gene-Related Peptide