GRANULOCYTE-COLONY-STIMULATING FACTOR ENHANCES BONE-MARROW STEM-CELL DAMAGE CAUSED BY REPEATED ADMINISTRATION OF CYTOTOXIC AGENTS

Despite the increasing use of cytokines to circumvent the acute dose-l imiting myelotoxicity of cancer treatment, little is known about the c ombined effects of cytotoxic agents and cytokines on the primitive ste m cells responsible for longterm hematopoiesis. In an experimental mod el, we administered cytotoxic agents that have variable effects on pri mitive stem cells in C57BL/6 (B6)-mice. Mice received six every-other- week doses of cyclophosphamide (CY, 84 mg/kg), VP-16 (24 mg/kg) + cisp latinum (2.4 mg/kg), carboplatinum (50 mg/kg), chlorambucil (12 mg/kg) , BCNU (13.2 mg/kg), or TBI (80 cGy). Granulocyte colony-stimulating f actor (G-CSF; 250 mu g/kg/day) was administered subcutaneously twice d aily on days 3 to 6 after each dose of the cytotoxic agent. Comparison with animals receiving the cytotoxic agent alone was made to investig ate the effects of G-CSF on long-term hematopoiesis. Hematopoiesis was measured 20 weeks after the last dose of the cytotoxic agent by asses sment of peripheral blood counts, marrow cellularity, progenitor cell content (colony-forming units-spleen; CFU-S), and primitive stem cell number (long-term repopulating ability and day 28 and day 35 cobblesto ne area-forming cell [CAFC] frequencies). Exposure to cytotoxic agents alone resulted in a significant decrease in primitive stem cells (as measured by repopulating units [RU] and day 28 and day 35 CAFC content ) in animals given carboplatinum, chlorambucil, BCNU, and TBI, but not in animals treated with cyclophosphamide or VP-16 and cisplatinum. Th e addition of G-CSF resulted in a significant decrease in stem cell co ntent when compared with no G-CSF administration in animals treated wi th chlorambucil, BCNU, or TBI. Thus, G-CSF administered after repeated exposure to cytotoxic agents, appeared to damage the primitive stem c ell compartment when used in combination with agents known to damage p rimitive stem cells. These results, although obtained in an experiment al model, should raise concerns for the indiscriminate use of G-CSF in the clinic. (C) 1998 by The American Society of Hematology.