期刊
BRITISH JOURNAL OF CANCER
卷 97, 期 11, 页码 1523-1531出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6604057
关键词
opioids; morphine; angiogenesis; cyclooxygenase-2; breast cancer; metastasis
类别
资金
- NCI NIH HHS [CA109582, R01 CA109582] Funding Source: Medline
- NHLBI NIH HHS [HL68802, R01 HL068802] Funding Source: Medline
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 (similar to 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.
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