Influence of timing of administration of 5-fluorouracil to donors on bone marrow engraftment in nonmyeloablated hosts.
We evaluated the engraftment and the cell cycle status of marrow cells at various times after 5-fluorouracil (5-FU) administration. 5-FU (150 mg/kg) was given to donor male BALB/c mice at 1, 2, 6, or 12 days prior to marrow harvest. The donor cells were then assessed in host nonmyeloablated female mice. Bone marrow engraftment of marrow treated with 5-FU was evaluated and compared to marrow treated with diluent (phosphate-buffered saline) at 3 and 10 weeks after marrow infusion. Our data show a rapid induction of an engraftment defect 1 day after 5-FU, persistence of this defect through day 6, and a recovery by day 12. Experiments using hydroxyurea (which selectively kills cells in the S phase) to determine the cell cycle status indicated that cells that engrafted in post-5-FU marrow were noncycling at days 1, 2, and 12 but cycling at day 6. Post-5-FU bone marrow was also analyzed in vitro by colony assays and its cycling status determined by 3H-thymidine suicide assay. High-proliferative-potential colony-forming cells (HPP-CFCs) and low-proliferative-potential colony-forming cells (LPP-CFCs) decreased rapidly 1 day after 5-FU, with a nadir observed at day 6 for HPP-CFCs and day 2 for LPP-CFCs. By day 12, LPP-CFCs showed a total recovery, but HPP-CFCs were still defective. Significant numbers of HPP-CFCs were cycling, mostly at days 6 and 8 after 5-FU, whereas LPP-CFCs appeared quiescent except at day 2. These results emphasize the importance of timing if post-5-FU marrow is used for gene therapy or marrow transplantation.
D'Hondt
L
L
Centre Hospitalier Notre-Dame et Reine Fabiola, Charleroi, Belgium. dhondt.lionel@chndrf.be
Carlson
J
J
Benoit
B
B
Reilly
J
J
Grimaldi
C
C
Wuu
J
J
Lambert
J F
JF
Dooner
M S
MS
Quesenberry
P J
PJ
D000818:Animals; D015139:Blotting, Southern; D001854:Bone Marrow Cells / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004261:DNA Replication; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000494:pharmacology; D006085:Graft Survival; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006918:Hydroxyurea / Q000494:pharmacology; D008297:Male; D051379:Mice
D005472:Fluorouracil; D006918:Hydroxyurea