Enhancing Effect of an Inhibitor of Nitric Oxide Synthesis on Bacillus Calmette-Guérin-induced Macrophage Cytotoxicity against Murine Bladder Cancer Cell Line MBT-2in vitro

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Abstract
We studied the effect of an inhibitor of nitric oxide (NO) synthesis, NG‐monomethyl‐L‐arginine (LNMMA), on the Bacillus Calmette‐Guérin (BCG)‐induced antitumor activity of murine peritoneal exudate cells (PEC) against murine bladder cancer cell line MBT‐2 in vitro. L‐NMMA enhanced BCG‐induced cytotoxic activity of PEC, as well as interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α production. The L‐NMMA‐induced enhancement was due to the prolonged survival of BCG in macrophages, because no enhancement of cytotoxicity was observed and neither IFN‐γ nor TNF‐α production was significantly enhanced by killed BCG. Anti‐TNF‐α antibody (Ab) and anti‐IFN‐γAb reduced the L‐NMMA‐induced enhancement of the cytotoxicity. The depletion of T cells from PEC reduced the production of both IFN‐γ and TNF‐α, as well as the enhancement of cytotoxicity induced by viable BCG plus L‐NMMA. These results suggest that L‐NMMA has an enhancing effect on BCG‐induced macrophage cytotoxicity and the enhancement is partially mediated by T cells and their soluble products. Accordingly, NO inhibitor should be a valuable adjunct to BCG immunotherapy for bladder cancer.

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