Influence of timing of administration of 5-fluorouracil to donors on bone marrow engraftment in nonmyeloablated hosts

• Published in: International journal of hematology Vol. 74; no. 1; pp. 79 - 85
• Main Authors: D'HONDT, Lionel, CARLSON, Jane, BENOIT, Brian, REILLY, Judith, GRIMALDI, Christina, WUU, Joanne, LAMBERT, Jean-Francois, DOONER, Mark S, QUESENBERRY, Peter J
• Format: Journal Article
• Language: English
• Published: Tokyo Springer 01.07.2001; Springer Nature B.V
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Blotting, Southern; Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Cell cycle; Cell Cycle - drug effects; Colony-Forming Units Assay; DNA Replication; Drug Administration Schedule; Female; Fluorouracil - administration & dosage; Fluorouracil - pharmacology; Graft Survival; Hematopoietic Stem Cells - drug effects; Hydroxyurea - pharmacology; Influence; Male; Medical sciences; Mice; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplants & implants; Animal model; Hydroxycarbamide; Stem cell; Hematopoietic cell; Homograft; Cell cycle; Bone marrow; Graft; Pretreatment; Fluorouracil; Enzyme; Transferases; Fluoropyrimidine derivatives; Rodentia; Enzyme inhibitor; Non myeloablative treatment; Thymidylate synthase; Vertebrata; Mammalia; Methyltransferases; Antimetabolic; Donor; Mouse; Animal; Engraftment; Pyrimidine derivatives; Timing
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/BF02982554

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.