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Pharmacological Studies Comparing the Mechanism of Tumor-Induced and Activated Macrophage-induced Bone Marrow Cytolysis¹

Departments of Research [G. B., R. L.] and Medicine [J. F. D., S. Z.], Veterans Administration Medical Center, Northport, New York 11768, and Department of Medicine [J. F. D., S. Z.], Health Sciences Center, State University of New York, Stony Brook, New York 11794

The Bacillus Calmette-Guérin-activated macrophage-induced marrow cytotoxicity assay and the tumor-induced marrow cytotoxicity assay were used to explore in vitro the similarities 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 cytotoxicity. Actinomycin D, an ineffective inhibitor of tumor-induced marrow cytotoxicity, was an effective inhibitor of macrophage-induced marrow cytotoxicity. The protein synthesis inhibitor, cycloheximide, was an effective inhibitor of macrophage-induced marrow cytotoxicity, but not tumor-induced marrow cytotoxicity. The protease inhibitor, N--p-tosyl-L-lysine chloromethyl ketone HCl, which has trypsin specificity, was found to be an effective inhibitor of both tumor- and macrophage-induced marrow cytotoxicity. Macrophage-induced marrow cytotoxicity, unlike tumor-induced marrow cytotoxicity, was also inhibited by soybean trypsin inhibitor and Trasylol. Macrophage- and tumor-induced marrow cytotoxicity were stimulated by dibutyryl cyclic adenosine 3':5'-monophosphate and by dexamethasone. The metabolic inhibitors, NaF and KCN, inhibited both macrophage- and tumor-induced marrow cytotoxicity. Macrophage-induced marrow cytotoxicity, unlike tumor-induced marrow cytotoxicity, was shown to be inhibited by ethylenediaminetetraacetic acid, suggesting that macrophage-mediated marrow cytolysis may be a calcium-magnesium-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 marrow 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.

¹ This research was supported by the Veterans Administration.

² To whom requests for reprints should be addressed.

Received 8/28/79. Accepted 1/16/80.