Yim C Y, Bastian N R, Smith J C, Hibbs J B, Samlowski W E
University of Utah Cancer Immunotherapy Program, Salt Lake City 84132.
Cancer Res. 1993 Nov 15;53(22):5507-11.
The role of macrophages in the host immune response against cancers remains uncertain. Since nitric oxide synthesis represents a significant macrophage antitumor mechanism in vitro, we evaluated whether NO was synthesized during the immune response to growing murine skin cancers. NO synthesis was readily detectable in enzymatically dissociated tumors (RD-995 and LR-298) and was inhibited by N omega-monomethyl-L-arginine (MLA) and by macrophage depletion. Nitrosylation of iron-sulfur and heme complexes was observed in these tumors using electron paramagnetic resonance spectroscopy. NO production in the presence of increasing concentrations of MLA correlated inversely with tumor cell proliferation in vitro. To elucidate the role of NO during in vivo tumor progression, tumor-bearing mice were treated with continuous infusions of the nitric oxide synthase inhibitor MLA. MLA-treated mice demonstrated increased growth and delayed rejection of the highly antigenic UV radiation-induced regressor tumor LR-298. These experiments demonstrate that macrophage-derived NO synthesis can contribute to the antitumor immune response in vivo.
巨噬细胞在宿主针对癌症的免疫反应中的作用仍不明确。由于一氧化氮合成在体外代表一种重要的巨噬细胞抗肿瘤机制，我们评估了在对生长中的小鼠皮肤癌的免疫反应过程中是否会合成一氧化氮。在酶解肿瘤（RD - 995和LR - 298）中很容易检测到一氧化氮合成，并且其受到Nω-单甲基-L-精氨酸（MLA）和巨噬细胞耗竭的抑制。使用电子顺磁共振光谱在这些肿瘤中观察到铁硫和血红素复合物的亚硝基化。在体外，随着MLA浓度增加，一氧化氮产生与肿瘤细胞增殖呈负相关。为了阐明一氧化氮在体内肿瘤进展过程中的作用，给荷瘤小鼠持续输注一氧化氮合酶抑制剂MLA进行治疗。接受MLA治疗的小鼠表现出高抗原性紫外线辐射诱导的消退型肿瘤LR - 298生长加快且排斥延迟。这些实验表明，巨噬细胞衍生的一氧化氮合成可在体内促进抗肿瘤免疫反应。
