Analysis of the stem cell sparing properties of cyclophosphamide

Cyclophosphamide was examined for its ability to spare the most primitive hematopoietic stem cell (PHSC).

C57BL6/J mice (Groups A and B) were sacrificed 24 h and 4-6 wk, respectively, after a single or second injection of low-dose cyclophosphamide (90 mg/kg) on days 1, 3, 7, or 15. A competitive repopulation assay was then performed, using B6-HbbdGpi-1a competitor cells, to determine the repopulating ability of exposed PHSC.

PHSC function was preserved after a single injection of cyclophosphamide and after a second injection on days 7 and 15 in both groups. In Group A, PHSC repopulating ability declined after a second injection on days 1 and 3 (p<0.05 only for day 1), as did repopulating units [RU]; PHSC numbers did not. In Group B, an insignificant decrease in repopulating ability and RU numbers was observed after a second injection on days 1 and 3, suggesting different etiologies for losses in the 2 groups, or correction of drug-induced defects within 1 month of cyclophosphamide administration. Total RU increased in single, day 1, 7 and 15 treatment groups. A significant number of marrow cells entered the S phase after cyclophosphamide dosing on day 3, and it is possible that a relationship exists between cell cycling and replicative damage. DNA damage was also increased 1 and 3 d after cyclophosphamide administration, although the significance of differences from controls was not definitive.

Low-dose cyclophosphamide can spare stem cells, depending upon the timing of subsequent doses.