5-FLUOROURACIL SPARES HEMATOPOIETIC STEM-CELLS RESPONSIBLE FOR LONG-TERM REPOPULATION

Abstract

The long-term immunohemopoietic reconstituting ability of bone marrow, treated with a single administration of 5-fluorouracil (5-FU), was measured to determine whether 5-FU caused any deleterious effect upon primitive stem cells (PSCs). Cells from 5-FU-treated marrow donors were mixed in four different proportions of total marrow contents with untreated competitor marrow containing genetically distinguishable hemoglobin (Hb) and glucosephosphate isomerase (GPI) transplantation markers. These cell mixtures were introduced into lethally irradiated hosts. The functional ability of the donor cell population was assessed by measuring the percentage of donor type Hb and GPI found in the host''s circulating erythrocytes and lymphocytes, respectively. Bone marrow from mice treated with 5-FU 1, 5, and 8 days prior to transplantation produced circulating lymphoid and erythroid cells as well as equal fractions of untreated fresh marrow when surveyed approximately 90 days after transplantation. Normal reconstitutive ability was thus maintained despite a tenfold reduction in marrow cell numbers when donor mice had been treated with 5-FU 5 days prior to transplantation. Donor marrow treated with 5-FU 15 days prior to transplantation had slightly decreased repopulating ability in one of two experiments. A second round of repopulation was stimulated subsequent to the initial 90-day screening by giving hosts a sublethal (500 rad) dose of irradiation. After 3-4 months, Hb and GPI parameters were the same as preirradiation values. Thus, the radioresistance of 5-FU treated PSCs remains comparable to that of fresh marrow, and their relative repopulating ability was not comprised by the additional stress of sublethal irradiation. After both rounds of repopulation the myeloid and lymphoid pathways were repopulated equally well by PSCs surviving 5-FU treatment. Repopulation of both pathways to the same extent suggests a common precursor as the proliferative agent. These results indicate that the PSCs were unaffected after a single treatment with 5-FU, although they were concentrated tenfold.