Role of SR-4987 stromal cells in the modulation of doxorubicin toxicity toin vitro granulocyte-macrophage progenitors (CFU-GM)

Bone marrow stromal microenvironment is essential for the maintenance of th e hematopoietic stem cell renewal both by cell-cell interaction and cytokin e production. However, stromal cells also exhibit drug metabolizing activit ies and they may accumulate the drug and successively affect hematopoietic progenitors by a retarded release. Our study investigated the role of both primary culture of murine bone marrow stroma and established stromal cells (SR-4987) in modulating the "in vitro" toxic activity of Doxorubicin (DXR) against murine granulocyte-macrophage progenitors (CFU-GM). The main part o f the study has been performed by a "in vitro" agar bilayer technique based on the CFU-GM assay performed over a feederlayer of stromal cells. The res ults suggest that bone marrow stromal cells play also an important role in decreasing the toxicity of Doxorubicin. Further SR-4987 stromal cells produ ce a Doxorubicin metabolite (not belonging to the series of metabolites des cribed in literature) which is completely ineffective in inhibiting the gro wth of CFU-GM and the activity of topoisomerase I. Our data suggest that bo ne marrow stromal cells must be considered as a cell population having oppo site pharmacological roles in modulating the drug toxicity on hematopoietic progenitors. In our model a mechanism of detoxification concerns the capac ity of SR-4987 stromal cells to inactivate the drug. For a better predictio n of drug hematotoxicity, it is very important to develop "in vitro" cell m odels able to discriminate between positive and negative modulation of drug toxicity that stromal cells can exert in the bone marrow microenvironment.