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Pharmacological Studies of the Mechanism of Tumor-induced Bone Marrow Cytolysis¹

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

The tumor-induced marrow cytotoxicity (TIMC) assay has been used in this study to explore in vitro the mechanism of cancer cell destruction of normal tissues. Previously, we have demonstrated that TIMC requires cell-cell contact. In this study, 1,3-bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard, agents that alkylate DNA, RNA, and proteins, were effective inhibitors of TIMC. Since agents that inhibit tumor cell DNA, RNA, and protein synthesis (doxorubicin, cis-dichlorodiammineplatinum(II), methotrexate, 5-fluorouracil, actinomycin D, and emetine) were ineffective in inhibiting TIMC, we evaluated the possibility that previously synthesized cellular proteins are mediating TIMC. The microtubule inhibitors, vincristine and colchicine, and the microfilament inhibitor, cytochalasin B, were ineffective in inhibiting TIMC. The protease inhibitor N--p-tosyl-L-lysine chloromethyl ketone HCl, which has a trypsin specificity, was found to be an effective inhibitor of TIMC. L-1-Tosylamide--phenylethyl chloromethyl ketone, a protease inhibitor with chymotrypsin specificity, marginally inhibited cytotoxicity. Trasylol, a broad-spectrum protease inhibitor; p-tosyl-L-arginine methyl ester HCl, a competitive inhibitor of proteases and esterases; soybean trypsin inhibitor, a potent plasmin and protease inhibitor; and -aminocaproic acid, a potent inhibitor of plasminogen activator did not inhibit TIMC. Dibutyryl cyclic adenosine 3':5'-monophosphate enhanced TIMC at all doses tested. This is consistent with the observation in other studies that dibutyryl cyclic adenosine 3':5'-monophosphate can increase both cell-bound and secreted enzyme activity. The necessity for intact cellular respiratory and energy-producing systems for TIMC was shown by the partial inhibition of TIMC by NaF and KCN. These data suggest to us that TIMC may be mediated by cellular proteins with serine protease activity.

¹ This research was supported by grant funds from the National Cancer Institute (CA 15629) and the Veterans Administration Medical Center (MR1S 9939-02).

² To whom requests for reprints should be addressed.

Received 7/31/78. Accepted 12/27/78.