Use of paired dose 5-fluorouracil as a conditioning regimen for marrow transplantation in a syngeneic mouse model. w

W. Goebel, Nancy Pech, Edward Srour, Mary C. Dinauer

Research output: Contribution to journalArticle

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Abstract

Traditional bone marrow transplantation models have utilized lethal (myeloablative) doses of radiation to condition the host. In humans, such conditioning is associated with multiple long-term side effects, including secondary malignancies. We have recently demonstrated =50% long-term donor chimerism in C57B1/6 mice transplanted with 20 x 10' fresh B6.SJL marrow cells after irradiation with 160 cGy. Because conditioning with antimetabolite drugs has the potential to further reduce toxicity, we studied 5-fluorouracil (5-FU) as a single conditioning agent. We gave C57B1/6 mice paired doses of 5-FU (150 mg/kg IP) on days 1 and 5, followed by transplantation of 20 x 106 fresh B6.SJL marrow cells on day 6. We observed no apparent toxicity from the conditioning. At 4 months post-transplant, donor chimerism averaged 37.7 ±11.2% (n=9), similar to that seen in 160 cGy conditioned mice. The long-term repopulating ability (LTRA) of paired dose 5-FU treated marrow was estimated using the competitive repopulation assay. Marrow from 5FU treated mice competed only =45% as well as fresh competitor marrow cells. We also examined the phenotype of paired dose 5-FU-treated marrow by flow cytometry. We found that the total marrow cell number and the number of Sea-1 Vlin cells was dramatically decreased by 48-72 hours after the second dose of 5-FU, similar to that observed after 1100 cGy radiation. In the 5-FU treated marrow, 12-25% of the Sca-l /lin cells were undergoing early apoptosis, as evidenced by annexin V and propidium iodide staining. These experiments show that paired dose 5-FU conditioning results in moderate level, stable long-term donor chimerism, and that both stem cell function and stem/progenitor cell number are reduced by paired dose 5-FU treatment. We are currently conducting experiments using paired dose 5-FU as a conditioning regimen for transplantation of retrovirally transduced marrow cells.

Original languageEnglish
JournalBlood
Volume96
Issue number11 PART I
StatePublished - 2000

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Fluorouracil
Transplantation
Bone Marrow
Chimerism
Cells
Stem Cells
Tissue Donors
Stem cells
Toxicity
Transplantation Conditioning
Cell Count
Radiation
Antimetabolites
Transplants
Flow cytometry
Propidium
Annexin A5
Bone Marrow Transplantation
Oceans and Seas
Dosimetry

ASJC Scopus subject areas

  • Hematology

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Use of paired dose 5-fluorouracil as a conditioning regimen for marrow transplantation in a syngeneic mouse model. w. / Goebel, W.; Pech, Nancy; Srour, Edward; Dinauer, Mary C.

In: Blood, Vol. 96, No. 11 PART I, 2000.

Research output: Contribution to journalArticle

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abstract = "Traditional bone marrow transplantation models have utilized lethal (myeloablative) doses of radiation to condition the host. In humans, such conditioning is associated with multiple long-term side effects, including secondary malignancies. We have recently demonstrated =50{\%} long-term donor chimerism in C57B1/6 mice transplanted with 20 x 10' fresh B6.SJL marrow cells after irradiation with 160 cGy. Because conditioning with antimetabolite drugs has the potential to further reduce toxicity, we studied 5-fluorouracil (5-FU) as a single conditioning agent. We gave C57B1/6 mice paired doses of 5-FU (150 mg/kg IP) on days 1 and 5, followed by transplantation of 20 x 106 fresh B6.SJL marrow cells on day 6. We observed no apparent toxicity from the conditioning. At 4 months post-transplant, donor chimerism averaged 37.7 ±11.2{\%} (n=9), similar to that seen in 160 cGy conditioned mice. The long-term repopulating ability (LTRA) of paired dose 5-FU treated marrow was estimated using the competitive repopulation assay. Marrow from 5FU treated mice competed only =45{\%} as well as fresh competitor marrow cells. We also examined the phenotype of paired dose 5-FU-treated marrow by flow cytometry. We found that the total marrow cell number and the number of Sea-1 Vlin cells was dramatically decreased by 48-72 hours after the second dose of 5-FU, similar to that observed after 1100 cGy radiation. In the 5-FU treated marrow, 12-25{\%} of the Sca-l /lin cells were undergoing early apoptosis, as evidenced by annexin V and propidium iodide staining. These experiments show that paired dose 5-FU conditioning results in moderate level, stable long-term donor chimerism, and that both stem cell function and stem/progenitor cell number are reduced by paired dose 5-FU treatment. We are currently conducting experiments using paired dose 5-FU as a conditioning regimen for transplantation of retrovirally transduced marrow cells.",
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