We are studying the regulation of H?2?O?2? secretory capacity in mononuclear phagocytes and mechanisms of tumor cell responses to this macrophage secretory product. In humans as in mice, the capacity of macrophages to secrete H?2?O?2? is induced by exposure to lymphokine. We will address the relation between this macrophage activating factor and interferon and analyze the enzymatic basis of the activated state. In contrast, tumor cells secrete a factor which has the opposite effect, that is, which markedly and specifically suppresses macrophage H?2?O?2?-releasing capacity. The same factor impairs the ability of macrophages to kill T. gondii and L. donovani, which usually are killed by activated macrophages, largely by oxidative mechanisms. We are studying the mechanism of action of this deactivating factor and its physicochemical properties. Finally, the antioxidant defense system of murine tumor cells, notably the glutathione redox cycle, plays an important role in the response of tumor cells to sulfhydryl-reactive antineoplastics as well as to macrophage-derived peroxide. We are analyzing the interaction of cysteine, glutathione, and sesquiterpene lactones, an approach which may provide a rationale for novel, synergistic therapeutic combinations. (MB)
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