Most primitive hematopoietic stem cells are stimulated to cycle rapidly after treatment with 5-fluorouracil

Abstract

To test whether primitive hematopoietic stem cells (PHSC) cycle rapidly during recovery from an initial 5-fluorouracil (5-FU) treatment, two doses of 5-FU were administered 1, 3, 5 or 8 days apart. Cells from treated marrow donors were mixed with untreated competitor marrow that would produce genetically distinguishable erythrocytes and lymphocytes, using hemoglobin (Hb) and glucosephosphate isomerase (GPI) transplantation markers. These cell mixtures were injected into lethally irradiated hosts. Functional abilities of donor marrow populations were assessed after 3, 6, and 12 months as percentages of donor type Hb and GPI in the host's circulating erythrocytes and lymphocytes, respectively. Bone marrow from mice treated with two doses of 5-FU 3 to 5 days apart was severely affected, producing circulating erythroid and lymphoid cells an average of only 25% of normal for doses 3 days apart, and 14% of normal for doses 5 days apart. Two doses of 5-FU administered 1 day or 8 days apart had much smaller effects, producing circulating cells 75% or 58% of normal. Thus, most PHSC are stimulated to proliferate rapidly 3 to 5 days after treatment with 5-FU, but far fewer PHSC proliferate as early as 1 day, or as late as 8 days, after the 5-FU treatment.