Enhancing effect of an inhibitor of nitric oxide synthesis on bacillus Calmette-Guerin-induced macrophage cytotoxicity against murine bladder cancer cell line MBT-2 in vitro.
We studied the effect of an inhibitor of nitric oxide (NO) synthesis, N(G)-monomethyl-L-arginine (L-NMMA), 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)-gamma and tumor necrosis factor (TNF)-alpha 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-gamma nor TNF-alpha production was significantly enhanced by killed BCG. Anti-TNF-alpha antibody (Ab) and anti-IFN-gammaAb reduced the L-NMMA-induced enhancement of the cytotoxicity. The depletion of T cells from PEC reduced the production of both IFN-gamma and TNF-alpha, 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.
Yamada
H
H
Department of Urology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan.
Matsumoto
S
S
Matsumoto
T
T
Yamada
T
T
Yamashita
U
U
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001500:BCG Vaccine / Q000276:immunology*; D002450:Cell Communication; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010844:Picibanil / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D013864:Thioglycolates / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000628:therapy*; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D000906:Antibodies; D000970:Antineoplastic Agents; D001500:BCG Vaccine; D004791:Enzyme Inhibitors; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D010844:Picibanil; D007371:Interferon-gamma