Evidence exists to demonstrate that the activation of macrophages enhances host defenses against neoplastic disease. The systemic activation of macrophages by immunomodulators in conjunction with conventional cancer chemotherapy is currently being tested in many experimental tumor models as a means to enhance resistance against tumor growth and metastases. Since many drugs used in cancer chemotherapy are also immunosuppressive, successful macrophage activation by immunomodulators necessitates that cancer chemotherapy also be minimally toxic to macrophages. Presently, there is little definitive information available regarding the influence of antitumor drugs on the macrophage activation process. This research will examine, in a rat model, the influence of selected immunosuppressive cancer chemotherapeutic drugs on the secretory and metabolic requirements related to the macrophage activation process. Rat peritoneal macrophages, activated in vivo with Corynebacterium parvum, will be harvested following the administration of agents used in cancer chemotherapy. The drugs used in this study will be methotrexate, cyclophosphamide, and glucocorticoids, antitumor agents with known suppressive actions on the macrophage. The effect of these antitumor agents on macrophage activation will be determined by measuring antibody-mediated cellular cytotoxicity (ADCC) and chemiluminescence activity as quantitative measures of macrophage functional and metabolic activation, respectively. Furthermore, the effects of these chemotherapeutic agents on the secretion by peritoneal and alveolar macrophages of superoxide anion and hydrogen peroxide, potentially toxic reactive oxygen intermediates, will also be examined. These studies will attempt to determine whether drugs used in cancer chemotherapy can impair secretory pathways that are potentially important to the tumoricidal activity of macrophages and, therefore, can limit tumor cell destruction by macrophages. Finally, the ability of in vivo and in vitro cancer chemotherapy to modify the activation-dependent stimulation of macrophage metabolism (i.e., glucose uptake and oxidation and protein synthesis) will also be investigated. The results of these studies will provide insight with respect to the regulation of macrophage metabolism pertinent to macrophage activation. Knowledge obtained from this work on how macrophage activation may be influenced by cancer chemotherapy will be vital for future clinical strategies regarding the use of immunomodulators in combination with cancer chemotherapy to augment nonspecific defense mechanisms against tumor growth and metastases. (IS)
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