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Cyclooxygenase-2 inhibition: A potential mechanism for increasing the efficacy of bacillus Calmette-Guerin immunotherapy for bladder cancer

Lookup NU author(s): Simon Dovedi, Professor John Kirby, Dr Helen Maitland, Dr Barry Davies, John Kelly

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Abstract

Purpose: Intravesical bacillus Calmette-Guerin (BCG) therapy is the principal treatment for high risk, noninvasive urothelial carcinoma and carcinoma in situ of the bladder. However, up to 40% of patients fail to respond to this treatment. In this study the potential for inhibition of PGE 2 production by BCG treated dendritic cells (DCs) was studied in the context of preferential polarization of the immune response toward a cancer clearing T-helper type 1 immune response. Materials and Methods: Murine bone marrow derived DCs were cultured with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. After 7 days the cells were stimulated with BCG. Cell surface expression of co-stimulatory molecules and phagocytic ability were measured by flow cytometry analysis to verify cell activation. The production of IL-10 and IL-12 was measured after DC stimulation with BCG in the presence of IL-10, prostaglandin E2 (Cayman Chemical, Ann Arbor, Michigan), antiIL-10 antibody (Insight Biotechnology, Wembley, United Kingdom), NS-398 and indomethacin (Sigma, Poole, United Kingdom). Results: Prostaglandin E2 stimulated a dose dependent increase in the levels of IL-10 produced by BCG activated DCs (p < 0.01). IL-10 significantly decreased IL-12 production (p < 0.001), while IL-10 blockade significantly increased IL-12 levels (p < 0.05). The COX-2 selective inhibitor NS-398 caused a dose dependent increase in the concentration of IL-12 produced by BCG activated DCs (p < 0.01). This effect was also seen with the partially selective COX-1 inhibitor indomethacin (p < 0.05). Conclusions: The inhibition of PGE2 synthesis by COX inhibition favored the production of IL-12 by BCG activated DC. This potentially will result in the generation of a T-helper type 1, polarized T-cell response that may improve the efficacy of BCG therapy. Copyright © 2005 by American Urological Association.


Publication metadata

Author(s): Dovedi SJ, Kirby JA, Atkins H, Davies BR, Kelly JD

Publication type: Article

Publication status: Published

Journal: The Journal of Urology

Year: 2005

Volume: 174

Issue: 1

Pages: 332-337

ISSN (print): 0022-5347

ISSN (electronic): 1527-3792

Publisher: Elsevier Inc.

URL: http://dx.doi.org/10.1097/01.ju.0000161589.85869.ae

DOI: 10.1097/01.ju.0000161589.85869.ae

PubMed id: 15947685


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