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 statistical analyses to estimate concentrations of primitive hematopoietic stem cells (PHSCs) in the marrow of mice after chemotherapy. Single doses of cyclophosphamide (CTX) from 80 to 200 mg/kg were administered to C57B16/J mice. Other treatment groups included mice given multiple doses of CTX at the lowest dose of 80 mg/kg; mice given four weekly doses of vincristine (VCR) or vinblastine (VBL); mice given two biweekly doses of bleomycin; mice receiving cytosine arabinoside (ARA) administered intraperitoneally thrice daily or as a continuous infusion by Alzet 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 of CTX exceeded 100 mg/kg. Decreases in PHSC function were usually associated with reductions in PHSC numbers; repopulating units, which include all repopulating cells, were similarly reduced. At the highest dose (33 mg/kg for 3 days), ARA caused a decline in marrow repopulating function. Drugs associated with mild clinical myelosuppression, such as VCR and VBI, did not significantly affect the repopulating ability of PHSCs, although VCR caused drastic declines in PHSC numbers. The marrow reconstitutive defects clinically-observed after chemotherapy may be caused partly by depletion of the PHSC pool.
Gardner
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RV
Louisiana State Medical Center, New Orleans 70112, USA.
Astle
C M
CM
Harrison
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DE
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003520:Cyclophosphamide