Duke S S, Schook L B, Holsapple M P
J Leukoc Biol. 1985 Apr;37(4):383-94. doi: 10.1002/jlb.37.4.383.
Dimethylnitrosamine (DMN) exposure altered the activity of the macrophage and natural killer (NK) cell defense mechanisms against the B16F10 melanoma in B6C3F1 adult female mice as assessed by several immunologic assays. Following 14 daily exposures (i.p.) to 1.5, 3.0, or 5.0 mg DMN/kg, mice were injected (i.v.) with B16F10 melanoma. The incidence and number of lung nodules, determined 18 days after challenge, were decreased in the DMN-exposed animals. The initial observation indicated the mice exposed to 3 mg/kg DMN were afforded the greatest protection. However, when mice exposed to the highest dose of DMN were divided into subgroups of mice with or without ascites, there was a degree protection seen in the 5-mg/kg-treated mice without ascites that was comparable to that of the 3-mg/kg group. The development of ascites is an overt toxic effect reflecting damage to the liver and was frequently associated with exposure to 5 mg/kg DMN. Exposure to DMN produced only slight changes in the activity of splenic NK cells as determined by the cytotoxicity of 51Cr-labelled YAC-1 cells. The activity was significantly increased only in mice exposed to 3 mg/kg DMN and only at effector:target (E:T) ratios of 30:1 and 10:1. Interestingly, the activity of the NK cells was significantly decreased at all E:T ratios in mice exposed to 5 mg/kg that developed ascites. The number of peritoneal exudate cells was decreased, albeit nonsignificantly, in a dose-related fashion. The phagocytic activity, as measured by the uptake of fluorescent latex beads, was increased in a dose-related fashion with significance noted at the highest dose of DMN. The role of the macrophage in the increased resistance to the tumor challenge was assessed with bone marrow derived macrophages. The cytostatic activity versus B16F10 tumor cells, as measured by the uptake of 3H-thymidine, was markedly increased in the bone marrow derived macrophages from DMN (5mg/kg) mice when compared to vehicle controls. These results suggest that exposure to DMN alters bone marrow, particularly the differentiation of effector tumoricidal cells, which renders the host more resistant to metastatic tumor formation.
通过多种免疫测定评估，二甲基亚硝胺（DMN）暴露改变了B6C3F1成年雌性小鼠巨噬细胞和自然杀伤（NK）细胞针对B16F10黑色素瘤的防御机制活性。在每天腹腔注射1.5、3.0或5.0 mg DMN/kg，连续14天之后，小鼠静脉注射B16F10黑色素瘤。在攻毒18天后测定的肺结节发生率和数量，在暴露于DMN的动物中有所降低。最初的观察表明，暴露于3 mg/kg DMN的小鼠获得了最大程度的保护。然而，当将暴露于最高剂量DMN的小鼠分为有腹水和无腹水的亚组时，在未出现腹水的5 mg/kg处理的小鼠中观察到了一定程度的保护，其程度与3 mg/kg组相当。腹水的出现是一种明显的毒性作用，反映了肝脏受损，并且经常与暴露于5 mg/kg DMN有关。通过51Cr标记的YAC-1细胞的细胞毒性测定，暴露于DMN仅使脾NK细胞活性产生轻微变化。仅在暴露于3 mg/kg DMN的小鼠中，且仅在效应细胞：靶细胞（E:T）比例为30:1和10:1时，活性才显著增加。有趣的是，在出现腹水的5 mg/kg暴露小鼠中，在所有E:T比例下NK细胞活性均显著降低。腹腔渗出细胞数量呈剂量相关方式减少，尽管不显著。通过荧光乳胶珠摄取测量的吞噬活性呈剂量相关方式增加，在最高剂量的DMN时具有显著性。用骨髓来源的巨噬细胞评估巨噬细胞在增强对肿瘤攻毒抵抗力中的作用。与载体对照相比，当用3H-胸腺嘧啶摄取测量时，来自DMN（5 mg/kg）小鼠的骨髓来源巨噬细胞对B16F10肿瘤细胞的细胞抑制活性显著增加。这些结果表明，暴露于DMN会改变骨髓，特别是效应杀瘤细胞的分化，这使宿主对转移性肿瘤形成更具抵抗力。
