Pharmacological studies comparing the mechanism of tumor-induced and activated macrophage-induced bone marrow cytolysis.

The Bacillus Ca/meffe-Gi/ér/n-activated macrophage-induced marrow cytotoxicity assay and the tumor-induced mar row cytotoxicity assay were used to explore in vitro the simi larities and differences between the mechanisms by which activated macrophages and cancer cells destroy normal cells in vivo. 1,3-Bis(2-chloroethyl)-1-nitrosourea, an agent that alkylates DNA, RNA, and proteins, is an effective inhibitor of tumor-induced and activated macrophage-induced marrow cy totoxicity. Actinomycin D, an ineffective inhibitor of tumor-in duced marrow cytotoxicity, was an effective inhibitor of mac rophage-induced marrow cytotoxicity. The protein synthesis inhibitor, cycloheximide, was an effective inhibitor of macro phage-induced marrow cytotoxicity, but not tumor-induced marrow cytotoxicity. The protease inhibitor, A/-a-p-tosyl-L-lysine chloromethyl ketone HCI, which has trypsin specificity, was found to be an effective inhibitor of both tumorand macrophage-induced marrow cytotoxicity. Macrophage-in duced marrow cytotoxicity, unlike tumor-induced marrow cy totoxicity, was also inhibited by soybean trypsin inhibitor and Trasylol. Macrophageand tumor-induced marrow cytotoxicity were stimulated by dibutyryl cyclic adenosine 3':5'-monophosphate and by dexamethasone. The metabolic inhibitors, NaF and KCN, inhibited both macrophageand tumor-induced mar row cytotoxicity. Macrophage-induced marrow cytotoxicity, un like tumor-induced marrow cytotoxicity, was shown to be in hibited by ethylenediaminetetraacetic acid, suggesting that macrophage-mediated marrow cytolysis may be a calciummagnesium-dependent process. Superoxide dismutase and catalase were ineffective inhibitors of cytotoxicity, suggesting that Superoxide and hydrogen peroxide do not cause marrow cytolysis. These data suggest that macrophage-induced mar row cytotoxicity, like tumor-induced marrow cytotoxicity, may be mediated by cellular proteins near or on the cell membrane and that both normal and neoplastic cells with cytolytic capacity share similar mechanisms for cell destruction.