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Amelioration of Chemotherapy‐Induced Toxicity by Cotreatment with AcSDKP, a Tetrapeptide Inhibitor of Hematopoietic Stem Cell Proliferation

Acute myelosuppression as a consequence of cytotoxic chemotherapy is well recognized as a dose-limiting factor in cancer treatment. Although other normal tissues may be adversely affected, bone marrow is particularly sensitive to the phase-specific agents. Self-renewing, pluripotent hematopoietic progenitor cells, or stem cells, as measured by spleen colony-forming units (CFU-S) are responsible for generation of the hematopoietic system.' In normal mice, such stem cells are mainly quiescent, and renewal of mature cells is provided by the partially differentiated, lineage-committed hematopoietic progenitors. At this stage, the stem cells are relatively invulnerable to phase-specific cytotoxic drugs that affect (i.e., kill) only those cells that are already in proliferation or about to begin proliferation. The stem cell compartment of the bone marrow that guarantees a sufficient supply of cells bound for differentiation, though mainly quiescent, still has approximately 10% of its cellular component in some state of mitosis.* During chemotherapy the first treatment kills proliferating malignant cells in the tumor as well as proliferating hematopoietic cells in the bone marrow, but has no effect on the quiescent CFU-S.