Effect of prolonged expansion of marrow progenitor compartments following doxorubicin (ADR) on subsequent radiation tolerance.
The long-term effects of a maximum tolerated dose of doxorubicin (ADR) (10 mg/kg, LD10/60) on the recovery of the hematopoietic compartments of the femoral marrow from radiation (450 rad) were investigated over a 32-week interval using a mouse model. Comparative radiation response curves, estimating hematopoietic proliferative potential, were used to establish response deficits (RD) for individual compartments of ADR-treated marrow. The RD data suggest that two potentially discrete lesions result from ADR treatment: one lesion associated with acute toxicity and a second developing 8-16 weeks after drug treatment. A depletion of the older hematopoietic stem cell (CFU-S8d) compartment was observed to accompany the development of the second lesion. Data are presented suggesting that both initial stem cell kill, as well as an accelerated aging of the CFU-S8d by prolonged expansion of progenitors, eventually lead to a depletion of stem cell reserve manifested by a progressive loss of radiotolerance with time.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011836:Radiation Tolerance / Q000187:drug effects*
D004317:Doxorubicin