The bone marrow microenvironment provides not only the primary site of normal postnatal hematopoiesis, but also the location of hematopoietic recovery following high dose chemotherapy or irradiation induced injury to the immune system. Reconstitution of the hematopoietic system requires efficient migration (homing) of transplanted progenitor cells to the bone marrow, and their subsequent support in stromal cell niches of the microenvironment. As treatment strategies for a variety of malignancies become increasingly aggressive, there is concern that endothelial and stromal cells that comprise the bone marrow microenvironment may be damaged by this therapeutic strategy. We noted a discrepancy in response to cytokine therapy in breast cancer patients treated with high-dose etoposide (VP-16), resulting in failure to respond to G-CSF therapy. In initial attempts to dissect the underlying mechanism, we demonstrated that VP-16 exposure resulted in dysreguation of expression of stromal cell cytokines, chemokines, and adhesion molecules. Our working hypothesis is that high dose VP-16 chemotherapy results in inefficient hematopoietic reconstitution due to reduced homing of transplanted progenitor cells to bone marrow and failure of cells in the marrow to interact appropriately with the hematopoietic microenvironment. The current proposal aims to further investigate specific mechanisms of hematopoietic failure in the presence of VP-16. We have focused on three key stromal cell products altered by etoposide treatment: vascular cell adhesion molecule-1 (VCAM-1), stromal cell derived factor-1 (SDF-1), and stem cell factor (SCF). We will also evaluate the effect of VP-16 on endothelial cells, and indirect effects on hematopoietic cells that result from failure to interact appropriately with chemotherapy damaged stromal cells. Our overall goal is to better understand the effect of dose intensive chemotherapy on mechanisms of normal hematopoeisis. Results from this investigation will aid in tailoring high dose chemotherapy regimens to maintain efficacy of tumor eradication but reduce damage to the hematopoietic microenvironment. These results may also be more broadly applied to our understanding of mechanisms of action of topoisomerase II inhibitors as therapeutic tools.
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