Pharmacological studies of the mechanism of tumor-induced bone marrow cytolysis.

activating activity in the cell-free supernatant (19—21 , 23, 34, 35) and bound to a particulate fraction of homogenized cells (7, 34) has been observed with virally transformed malignant fibroblasts. Plasminogen-independent fibrino lytic activity has also been demonstrated in Rous sarcoma virus-transformed chick embryo fibroblasts (6). In a recent report (40), we have described a new experi mental model to study cancer invasiveness in vitro. Using 59Fe-labeled rat bone marrow cells as the target cells and cocultured W-2563 cells as the effector cells, we were able to assess cancer-induced marrow cytotoxicity. The cyto toxic effect on marrow cells was noted after 8 hr of coincu bation with tumor cells and required continuous cell-cell interaction. In the current study, we have examined the effects of various pharmacological inhibitors on TIMC in order to help characterize the mechanism of cancer-me diated destruction of normal cells. In view of previous evidence that W-256 cancer cells are relatively resistant to many pharmacological agents, we chose to study the ef fects of drugs on DNA, RNA, and protein synthesis as well as cytotoxicity. The data demonstrated that TIMC is highly resistant to most chemotherapeutic agents except high dose alkylating agents. A possible role for plasminogen independent cell-bound serine protease activity is sug gested by the effectiveness of the protease inhibitor TLCK in inhibiting TIMC.