Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362.
Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362.
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发表时间：
1995-07
期刊：
影响因子：
11.2
通讯作者：
K. Xie;Shile Huang;Z. Dong;M. Gutman;I. Fidler
中科院分区：
文献类型：
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作者：
K. Xie;Shile Huang;Z. Dong;M. Gutman;I. Fidler
本研究的目的是确定诱导型一氧化氮合酶（iNOS）的激活是否可以作为免疫抑制剂治疗小鼠网状细胞肉瘤转移的靶点。通过将M5076细胞静脉内注射到同系C57 BL/6小鼠中建立肝转移。多次全身给予含有脂肽CGP 31362（MLV-31362）或MLV-31362联合鼠IFN-γ的多层囊泡-脂质体（MLV）可根除转移瘤。肿瘤消退与通过北方印迹和免疫组织化学技术检测的肿瘤病变内的iNOS表达以及一氧化氮（NO）的产生增加相关。一个特定的iNOS抑制剂，NG-甲基-L-精氨酸的管理，显着降低NO的生产和免疫调节剂的抗肿瘤活性减弱。与肝转移的消退一致，MLV-31362和IFN-γ联合在体外和体内条件下协同诱导肿瘤细胞中的iNOS基因表达、NO产生和细胞凋亡。NMA的加入抑制了NO的产生和细胞凋亡。这些数据表明，MLV-31362 + IFN-γ多次全身给药可激活肉瘤细胞中的内源性iNOS，然后进行细胞凋亡，进而导致M5076肉瘤肝转移消退。
The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (iNOS) can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma metastases. Liver metastases were established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) containing the lipopeptide CGP 31362 (MLV-31362) or MLV-31362 combined with murine IFN-gamma eradicated the metastases. Tumor regression correlated with iNOS expression within the tumor lesions detected by Northern blot and immunohistochemistry techniques and with increased production of nitric oxide (NO). The administration of a specific iNOS inhibitor, NG-methyl-L-arginine, significantly decreased NO production and diminished the antitumor activities of the immunomodulators. Consistent with the regression of hepatic metastases, the combination of MLV-31362 and IFN-gamma synergistically induced iNOS gene expression, NO production, and apoptosis in the tumor cells under in vitro and in vivo conditions. The addition of NMA prevented the production of NO and apoptosis. These data imply that multiple systemic administrations of MLV-31362 plus IFN-gamma activate endogenous iNOS in sarcoma cells, which then undergo apoptosis, leading in turn to the regression of M5076 sarcoma hepatic metastases.