HEMATOPOIETIC PRECURSOR CELL EXHAUSTION IS A CAUSE OF PROLIFERATIVE DEFECT IN PRIMITIVE HEMATOPOIETIC STEM-CELLS (PHSC) AFTER CHEMOTHERAPY

The authors used the competitive repopulation assay and simple statist ical analyses to estimate concentrations of primitive hematopoietic st em cells (PHSCs) in the marrow of mice after chemotherapy. Single dose s of cyclophosphamide (CTX) from 80 to 200 mg/kg were administered to C57B16/J mice. Other treatment groups included mice given multiple dos es of CTX at the lowest dose of 80 mg/kg; mice given four weekly Close s of vincristine (VCR) or vinblastine (VBL); mice given two biweekly d oses of bleomycin; mice receiving cytosine arabinoside (ARA) administe red intraperitoneally thrice daily or as a continuous infusion by Alze t pump for 3 days; and controls given no drug. The lowest dose of CTX (80 mg/kg), given once or repeatedly, spared PHSC numbers and function . The functional capacity of PHSCs declined significantly once doses o f CTX exceeded 100 mg/kg. Decreases in PHSC function were usually asso ciated with reductions in PHSC numbers; repopulating units, which incl ude all repopulating cells, were similarly reduced. At the highest dos e (33 mg/kg for 3 days), ARA caused a decline in marrow repopulating f unction. Drugs associated with mild clinical myelosuppression, such as VCR and VBL, did not significantly affect the repopulating ability of PHSCs, although VCR caused drastic declines in PHSC numbers. The marr ow reconstitutive defects clinically-observed after chemotherapy may b e caused partly by depletion of the PHSC pool.