People with cancer abuse alcohol. While 20% w/v alcohol consumed in the drinking water generally suppresses the immune response paradoxically decreases metastasis of murine B16BL6 melanoma, a very invasive and metastatic cell line. Interferon gamma (IFN-gamma) produced by natural killer (NK) and NKT cells and possibly memory T cells is essential to control metastasis of melanoma. Preliminary data indicate that alcohol consumption significantly increases the percentage of NKT cells in the periphery and the percentage of IFN-gamma producing NKT and T memory cells to reduce metastasis. Alcohol consuming mice die prematurely even though metastasis is inhibited and the mechanisms associated for this decrease in survival will be investigated. Thus, it is hypothesized that the antimetastatic effect of chronic alcohol consumption is due to increased production of IFN-gamma by NKT and memory T cells. It is further hypothesized that alcohol consumption decreases survival through a combination of effects on altering T cell survival, hypoglycemia, and oxidative stress. To test these hypotheses, we propose the following specific aims: 1. Determine the contributions of NKT cells and T cells to the mechanism by which alcohol consumption inhibits melanoma metastasis 2. Determine the effect of alcohol on metastasis of other animal tumor models. 3. Determine the mechanisms associated with decreased survival of alcohol consuming, melanoma-bearing mice. Alcohol will be fed to female C57BL/6, NKT knockout, IFN-gamma knockout, and nude mice to assess the mechanisms associated with inhibition of melanoma metastasis. Experimental and spontaneous metastasis assays also will examine metastasis of RM-1 prostate cancer and 3LL Lewis lung carconima in appropriate alcohol- consuming murine models. Flow cytometric and ELISA assays will be used to determine lymphocyte populations, surface and intracellular marker expression, cytokine producing cells, and cytokine concentrations.
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