Effect, With Time, of Melphalan on Hematopoietic Stem Cells Proliferating at Different Rates

Abstract

The response, with time, of mouse hematopoietic colony-forming units (CFU) after in vivo exposure to the aromatic nitrogen mustard derivative melphalan was investigated. Normal, slowly proliferating CFU showed an initial depression within 2–4 hours after administration of the drug, followed by a second prolonged fall reaching a minimum survival at 48 hours. Although the 4-hour survival of rapidly proliferating CFU was lower than for normal CFU, no second fall was observed. As a result, the differential sensitivity of slowly and rapidly proliferating CFU to melphalan, and hence the proliferation dependency of this agent, was a function of time of the assay. Several possible reasons for the second fall in normal CFU were investigated. A leakage of CFU into the peripheral blood, the prolonged availability of active melphalan or toxic metabolites, changes in CFU seeding efficiency, or the loss of CFU through differentiation to mature hematopoietic cells cannot explain the second fall in CFU after melphalan.