The bone marrow is an important dose-limiting cell renewal tissue for chemotherapy, radiation therapy, and bone marrow transplantation (BMT). The objectives of this ongoing project are to study the stem cell compartment of the bone marrow, its functional organization, and the implications of this organization on the clinical use of cytotoxic agents, cytokines, and radiation. This project is also directed toward improving autologous BMT by optimizing donor marrow engraftment and long-term hematopoiesis and survival of recipients. To continue these objectives we will characterize donor marrow stem cell subpopulations responsible for providing short-term engraftment and long-term hematopoiesis after transplantation, evaluate the ability of selected radioprotective and chemoprotective agents to protect the earliest stem cells, and define the effects of high dose cytotoxic agents and TBI on the host stem cells and microenvironment. Re-establishment of normal hematopoiesis following BMT occurs in two phases. Initial recovery of peripheral blood counts appears to be mediated by late stem and progenitor cells. Long-term maintenance of hematopoiesis is due to more primitive stem cells. Many autologous BMT candidates have had extensive prior exposure to chemotherapy which may damage these subpopulations. Using a murine autologous BMT model and both in vivo and in vitro stem cell assays, we will determine the relationship between changes in stem cell subpopulation distribution and ability to engraft and provide long-term hematopoiesis and recipient survival for donor marrows previously exposed to various cytotoxic agents. Cytokine therapy is becoming increasingly utilized to speed hematopoietic recovery after high dose chemotherapy and BMT. Studies will be performed to evaluate the effects of four cytokines (I.-1, IL-3, IL-6, and G-CSF) on bone marrow stem cell content and self-renewal following chemotherapy or BMT. Some of these cytokines also demonstrate radioprotective effects on the bone marrow. The radioprotective capacity of IL-1 and G-CSF for primitive stem cells will be evaluated. AcSDKP, an inhibitory synthetic tetrapeptide, has been shown to protect hematopoietic stem cells from cycle-active drugs. This agent will be further investigated for its ability to protect primitive marrow stem cells from radiotherapy and other cytotoxic agents. The acute myelotoxicity following high dose TBI, chemotherapy, or radioimmunotherapy regimens used to treat patients with advanced malignancies can be circumvented by autologous bone marrow rescue. The influence of these treatment regimens on the earliest host stem cells, on the supporting microenvironment, and on donor marrow engraftment will be determined. Little is known of the factors most important for obtaining long-term engraftment of autologous donor marrow in the clinic. This is due to the lack of a primitive stem cell assay for human marrow, and the absence of markers to measure autologous marrow engraftment. Most high dose chemotherapy programs do not totally ablate the host hematopoietic stem cells, and it is not known whether residual host or engrafted donor hematopoietic stem cells provide the host with long-term hematopoietic support. The ability to directly measure host stem cell ablation, and to evaluate the quality of donor marrow engraftment by self-renewal and survival assays in the mouse should provide answers to many questions concerning autologous BMT in the clinic.
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