The tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a potent inhibitor of hematopoietic stem cell proliferation. We examined the effects of AcSDKP on the production of granulocyte-macrophage colony-forming cells (CFU-GM) and high proliferative potential colony-forming cells (HPP-CFC) in human long-term bone marrow (LTBM) cultures and CFU-GM and erythroid burst-forming cells (BFU-e) in short-term liquid cultures. The addition of AcSDKP in short-term bone marrow cultures resulted in a maximum depression of the total number of progenitor cells as well as the number of progenitor cells entering cell cycle following culture with 10-12 to 10-14 M AcSDKP and 10-14 M AcSDKP when exogenous cytokines (GM-CSF, IL-3, or SCF) were added. AcSDKP was added daily to LTBM cultures at various concentrations (10-8 M to 10-16 M) for up to 5 weeks. In these LTBM culture studies, AcSDKP inhibited the entry of nonadherent progenitor cells into S phase and decreased the number of nonadherent progenitor cells with peak activity at 10-12 M. In contrast, AcSDKP had no effect on the number of adherent CFU-GM, HPP-CFC, or cellularity per culture or percent of adherent progenitor cells in S phase. These studies indicate that the concentration of the tetrapeptide is critical to the activity of AcSDKP on human hematopoietic progenitor cells. Furthermore, we report that the presence of cytokines or stromal cells also affects the response of progenitor cells to AcSDKP. These results will aid in determining kinetic properties of AcSDKP for the development of clinical protocols to protect normal human hematopoietic stem and progenitor cells following cycle-specific chemotherapy agents.
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