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Effects of N-nitrosodimethylamine on tumor susceptibility
Abstract:
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.
Insights
Dimethylnitrosamine (DMN) exposure enhanced anti-tumor immunity in mice, reducing melanoma metastasis. Macrophage activity increased, suggesting DMN may reprogram immune cells for improved tumoricidal function.
Area of Science:
- Immunology
- Toxicology
- Cancer Research
Background:
- Dimethylnitrosamine (DMN) is a known toxicant.
- The impact of DMN on immune mechanisms against cancer is not fully understood.
- B16F10 melanoma is a common model for studying anti-tumor immunity.
Purpose of the Study:
- To investigate the effects of DMN exposure on immune cell activity.
- To assess DMN's influence on the host's defense against B16F10 melanoma.
- To determine if DMN exposure can enhance resistance to metastatic tumor formation.
Main Methods:
- Mice were exposed to varying doses of DMN (1.5, 3.0, 5.0 mg/kg) daily for 14 days.
- Mice were subsequently challenged with B16F10 melanoma cells.
- Immunologic assays were used to evaluate macrophage and natural killer (NK) cell activity, and tumor burden (lung nodules).
- Bone marrow-derived macrophages were assessed for cytostatic activity against tumor cells.
Main Results:
- DMN exposure decreased the incidence and number of lung nodules in a dose-dependent manner.
- The 3 mg/kg DMN dose showed the greatest protection; however, 5 mg/kg DMN without ascites also provided significant protection.
- Splenic NK cell activity showed minimal changes, with a significant increase only at 3 mg/kg DMN.
- Macrophage phagocytic activity increased with DMN dose, and bone marrow-derived macrophages exhibited enhanced cytostatic activity against B16F10 cells.
- Ascites development, a sign of liver toxicity, was associated with the highest DMN dose.
Conclusions:
- DMN exposure modulates immune responses, enhancing resistance to B16F10 melanoma metastasis.
- The study suggests DMN alters bone marrow differentiation, promoting tumoricidal effector cells.
- Macrophages appear to play a key role in the observed anti-tumor effects of DMN.