Advances in Brief In Vivo Cisplatin-exposed Macrophages Increase Iminunostimulant-induced Nitric Oxide Synthesis for Tumor Cell Killing1

Mice pee-exposed to cisplatin increased their production of nitric oxide (NO) when treated with lipopolysaccharide (LPS). Peritoneal macrophages, isolated from mice 11 days after Cisplatin treatment and cultured with LPS plus WN-y, increased NO production, whereas the macrophages Lsolated 2 days after cisplatin treatment decreased it. In both cases, NO was not pro duced without immunostimulant(s). Northern and Western Blot analysis showed that macrophagesexposedto cisplatinfor 11 days increasedproduc tion of mRNA and protein expression of inducible nitric oxide synthase (iNOS).Thisresultindicatedthat macrophagesbecamemoresensitiveto LPS and WN-y when they were exposed to CiSplatinin vivo. Peritoneal macro phages, when activated with LPS plus WN-y and then cocultured with several tumorcells, exhibited cytotoxicactivity against both cisplatin-sensitive and cisplatin-resistant tumor cells. There was no difference in CytOtOxicity between the paired cells. Under the same experimental condition, macro phagesthat wereexposedto cisplatinfor 11dayshad significantlyincreased their CytOtOXiCityto the tumor cells. This cytotoxic activity was inhibited by the NOS inhibitor NG@monomethy1@L@arginine, indicating that NO is a major effector for macrophage-mediated tumor cell kilhing@Treatment of tumor cells with S-nitroso-N-acetylpenicillamine, a NO-generating compound, showed the similar tumoricidal effect. These data demonstrated that injection of cisplatin into the mice can enhance the sensitivityof macrophagesto the subsequent treatment of immunostimulant(s) for effective tumor cell killing through enhanced NO production.