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Post-5-fluorouracil human marrow: stem cell characteristics and renewal
properties after autologous marrow transplantation
FM Stewart, D Temeles, P Lowry, T Thraves, WW Grosh and PJ Quesenberry
Division of Hematology/Oncology, University of Virginia Health Sciences
Center, Charlottesville.
The effect of 5-fluorouracil (5-FU) pretreatment on human bone marrow (BM)
progenitor/stem cells and recovery of hematopoiesis after autologous marrow
transplant was studied. Twenty-one patients were treated with 5-FU (15
mg/kg to 45 mg/kg) intravenously (IV) for 1 to 3 days administered 6 to 22
days before BM harvest. Post-FU marrow was infused into 15 patients after
high-dose cyclophosphamide, carmustine (BCNU), and VP-16 (CBV). Seventeen
patients (historical controls) were treated with CBV and autologous BM
transplantation but did not receive 5-FU before marrow harvest. The groups
were comparable for diagnosis and prior therapy. In the 5-FU-treated group
and control group, median recovery times for platelet count to 50,000/mm3
were 20 and 30 days, respectively (P = .007), and for platelet count to
100,000/mm3, 23 and 38 days, respectively (P = .007), while neutrophil
recovery was not significantly altered. In vitro cultures with 1 to 7
growth factors (interleukin-1 [IL-1], IL-3, IL-4, IL-6, colony-stimulating
factor-1 [CSF-1], granulocyte-macrophage colony-stimulating factor
[GM-CSF], and G-CSF) were performed. In 8 of 10 patients whose marrow was
studied before and after 5-FU treatment, the numbers of CFU-C responsive to
the combination of GM-CSF and IL-3 was increased 6.15-fold by 5-FU
pretreatment. In 4 of these patients, thymidine suicide of GM-CSF- and
IL-3-stimulated CFU-C ranged from 17% to 42%. High proliferative potential
colony-forming cell (HPP-CFC) was observed in low frequency in normal
marrow and patient's marrow before 5-FU treatment. In 11 of 16 patients
pretreated with 5-FU, increased numbers of HPP-CFC were noted. GM-CSF and
IL-3 interacted synergistically to stimulate HPP-CFC. Multifactor
combinations, especially GM-CSF + G-CSF + IL-3 + IL-6 + IL- 1 + CSF-1 did
not increase total colony count or classic HPP-CFC but did result in
altered morphology, producing huge, loose colonies. The marrow from
patients pretreated with 5-FU is enriched with multifactor- responsive
HPP-CFC, renews in vivo granulopoiesis in a manner comparable with marrow
harvests without 5-FU pretreatment, and provides accelerated in vivo
platelet recovery. This marrow may be an appropriate target marrow for gene
insertion in gene-therapy protocols.
Volume 81,
Issue 9,
pp. 2283-2289,
05/01/1993
Copyright © 1993 by The American Society of Hematology
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