Celecoxib, an inhibitor of Prostaglandin E(2) (PGE(2)), is a potent immune modulator in the treatment of urothelial cancer. PGE(2) is known to suppress both tumor antigen-specific helper T (T(H)1) cells and the generation of cytotoxic T lymphocytes (CTLs). It is hypothesized that a combination of the cyclooxygenase 2 (COX-2) selective inhibitor celecoxib and intravesical bacillus Calmette-Guérin (BCG), an effective tumor immunoprophylaxis and ablative therapy for non-muscle-invasive bladder cancer, would be more effective than BCG alone.
To test This hypothesis Dovedi and colleagues in University of New Castle, assessed urinary levels of PGE(2) in humans receiving BCG and in a murine model of urothelial cell carcinoma (UCC). The cytokine response to BCG plus celecoxib was assessed in murine dendritic cells (DCs) in vitro and tumor ablation was assessed in an orthotopic MBT2 murine bladder cancer model. Administration of intravesical BCG resulted in elevated urinary PGE(2) levels in patients with high-grade superficial UCC and in a mouse model of UCC. Activation of DCs with BCG stimulated COX-2 up-regulation and release of PGE(2) and interleukin 10. In a superficial mouse model of UCC, combination of celecoxib and intravesical BCG therapy resulted in increased tumor infiltration of CD4(+) T cells and improved efficacy when compared to BCG alone.
The authors concluded that a combination strategy involving BCG immunotherapy and celecoxib may be more therapeutically beneficial than stand-alone intravesical therapy.
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