CYTOKINES AS ENDOGENOUS MEDIATORS OF CANCER CACHEXIA

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Anorexia, weight loss and cachexia are the most visibly recognizable symptoms associated with cancer. However, the causes of cancer cachexia remain unknown. This application proposes that the anorexia, losses of lean tissue and body fat, and the hepatic acute phase response in patients or experimental animals with cancer can be attributed in part to an inappropriate or excessive production of cytokines, including interleukin-1 alpha or beta (IL-1), tumor necrosis factor-alpha (TNF-alpha/cachectin) and/or interleukin-6 (interferon-beta2). Experimental evidence suggests that either the tumor itself or tumor-infiltrating macrophages and other accessory cells, blood monocytes, or macrophages contained in organs of the reticuloendothelial system may be spontaneously releasing one or more of these cytokines. Therefore, in this application, cytokine production (IL- 1. TNF-alpha and IL-6) will be evaluated directly in the tumors of cachectic mice and of weight-losing patients by measuring both the quantity of cytokine-specific mRNA and immune reactive protein present, and from organs of the reticuloendothelial system of tumor-bearing mice. In addition, to determine whether the production of one or more of these cytokines is contributing directly to the development of cancer cachexia, specific neutralizing polyclonal and monoclonal antibodies directed against these cytokines and/or their tissue receptors will be administered in vivo to tumor-bearing mice in order to determine whether blocking the actions of these cytokines can either reduce the severity of or prevent the development of cancer cachexia. Thus, the specific goal of this application is to determine whether tumor specific or associated cytokine production are common findings in experimental and human cancer, whether the cytokines are of tumor or host origin, and finally, whether the host changes in food intake, carcass protein and fat composition, and hepatic acute phase response can be attributed to the inappropriate production of these cytokines.