Intravenous dose titration of busulfan in histocompatible mouse bone marrow transplantation

Robert Lannone, Leo Luznik, Sherrie Tennessee, Ephraim J. Fuchs

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Mixed hematopoietic chimerism can be induced by the transplantation of allogeneic marrow following conditioning with reduced doses of total body irradiation or oral busulfan. Oral busulfan can have variable absorption, leading to a high variation in blood drug levels and unpredictable effects on myelotoxicity. We therefore tested the effects titrating the dose of intravenous busulfan (Busulfex) on donor chimerism in a model of syngeneic bone marrow transplantation in mice. C57/BL6 (H-2b, CD45.2) recipients were given 5, 10, 20 and 30mg/kg on day -2, or 20mg/kg of intravenous Busulfex on days -2 and -1. The 40mg/kg dose was split because mice that received a single dose of 40mg/kg became acutely ill. All mice received ten million B6.SJL (H-2b, CD45.1) bone marrow (BM) cells on day 0. Using these congenic mouse strains allowed for discrimination of donor cells by staining with antibody to CD45.1. Control mice received ten million BM +/-100 cGy total body irradiation (day -1 ). Donor engraftment was measured at 10 weeks by flow cytometry using peripheral blood double stained for CD45.1 with fluorescein (Fi) and CD 11 (phagocytic lineage) with biotin-streptavidinphycoerythrin (PE). Results of donor engraftment and standard errors are shown in the table below. Group N % Mean Donor Engraftment (+/- SEM) 10 million BM 4 0.25(0.14) 100 cGy plus 10 million BM 5 6(5.25) Busulfex 5mg/kg plus 10 million BM 5 0.4(0.19) Busulfex 10mg/kg plus 10 million BM 5 0.7 (0.37) Busulfex 20mg/kg plus 10 million BM 5 12.2(10.7) Busulfex 30mg/kg plus 10 million BM 5 43.4(18,3) Busulfex 40mg/kg plus 10 million BM 5 64(13.4) Donor engraftment represents the proportion of CD11 positive cells that were also of the donor CD45 type (CD45.1) Summary: 1 .The myeloablative dose of intravenous Busulfex is greater than 40mg/kg in mice. 2.The maximally tolerated single dose of intravenous Busulfex in mice appears to be 30mg/kg. Conclusion: Mixed hematopoietic chimerism can be achieved by transplanting donor marrow following conditioning with non-myeloablative doses of Busulfex. Therefore, Busulfex may be considered as a substitute for total body irradiation in non-myeloablative conditioning regimens for alloBMT in humans.

Original languageEnglish (US)
Pages (from-to)300b
Issue number11 PART II
StatePublished - Dec 1 2000

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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