title: COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia.
abstract: Morphine and its congener opioids are the main therapy for severe pain in cancer. However, chronic morphine treatment stimulates angiogenesis and tumour growth in mice. We examined if celecoxib (a cyclooxygenase-2 (COX-2) inhibitor) prevents morphine-induced tumour growth without compromising analgesia. The effect of chronic treatment with celecoxib (by gavage) and/or morphine (subcutaneously), or PBS on tumour prostaglandin E(2) (PGE(2)), COX-2, angiogenesis, tumour growth, metastasis, pain behaviour and survival was determined in a highly invasive SCK breast cancer model in A/J mice. Two weeks of chronic morphine treatment at clinically relevant doses stimulates COX-2 and PGE(2) (4.5-fold compared to vehicle alone) and angiogenesis in breast tumours in mice. This is accompanied by increased tumour weight ( approximately 35%) and increased metastasis and reduced survival. Co-administration of celecoxib prevents these morphine-induced effects. In addition, morphine and celecoxib together provided better analgesia than either agent alone. Celecoxib prevents morphine-induced stimulation of COX-2, PGE(2), angiogenesis, tumour growth, metastasis and mortality without compromising analgesia in a murine breast cancer model. In fact, the combination provided significantly better analgesia than with morphine or celecoxib alone. Clinical trials of this combination for analgesia in chronic and severe pain in cancer are warranted.
authors.affiliation: 1Division of Hematology, Oncology and Transplantation, the Vascular Biology Center, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: M
authors.initials: M
authors.lastname: Farooqui
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: T
authors.initials: T
authors.lastname: Rogers
authors.forename: T
authors.initials: T
authors.lastname: Poonawala
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: C W
authors.initials: CW
authors.lastname: Song
authors.forename: K
authors.initials: K
authors.lastname: Gupta
mesh_terms: D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology* / Q000633:toxicity; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden
chemical_list: D000701:Analgesics, Opioid; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D009020:Morphine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone