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In vivo administration of recombinant methionyl human stem cell factor
expands the number of human marrow hematopoietic stem cells
J Tong, MS Gordon, EF Srour, RJ Cooper, A Orazi, I McNiece and R Hoffman
Hematology-Oncology Section, Indiana University School of Medicine,
Indianapolis 46202-5121.
A growing number of in vitro studies suggest that recombinant human stem
cell factor (SCF) is capable of augmenting the proliferative capacity of
human hematopoietic progenitor cells (HPC) and stem cells (HSC). We further
evaluated this biologic effect by analyzing the response of bone marrow
(BM) HPCs and HSCs to the administration of SCF in eight patients with
locally advanced or metastatic breast cancer who were enrolled in an
ongoing phase I study. SCF was administered for 14 days by daily
subcutaneous injection at dosages of 10, 25, or 50 micrograms/kg/d. BM
CD34+ HLA-DR+ and CD34+ HLA-DR- CD15- cells, previously shown by our
laboratory to be enriched for various classes of differentiated and
primitive HPCs, respectively, were quantitated in BM samples on day 0
(pretreatment) and day 15 (posttreatment). These CD34+ HLA-DR+ and CD34+
HLA-DR- CD15- cells were then isolated by cell- sorting and assayed for
several classes of HPCs, including the high-- proliferative potential
colony-forming cell (HPP-CFC), the burst- forming unit--megakaryocyte
(BFU-MK), and the long-term BM culture-- initiating cell (LTBMC-IC). SCF
administration resulted in a 3.3-fold (range, 1.4- to 18.8-fold; P = .018)
increase in the absolute numbers of CD34+ cells, a 3.7-fold (range, 1.2- to
8.2-fold; P = .028) increase in the absolute numbers of CD34+ HLA-DR+
cells, and a 2.4-fold (range, 1.1- to 29.3-fold; P = .010) increase in the
absolute numbers of CD34+ HLA-DR- CD15- cells. Following the infusion of
SCF, a statistically significant increase in the absolute numbers of
HPP-CFC (P = .018), BFU- MK (P = .046), CFU-granulocyte, erythrocyte,
monocyte, megakaryocyte (CFU-GEMM: P = .043), BFU-erythrocyte (BFU-E; P =
.043), CFU- granulocyte, macrophage (CFU-GM; P = .045), and
CFU-megakaryocyte (CFU- MK; P = .028) per milliliter of marrow was
observed. Stromal cell-free LTBMCs supplemented with SCF and interleukin-3
(IL-3), initiated with CD34+ HLA-DR- CD15- cells obtained on day 0,
produced viable cells for 9.6 weeks, compared with 11.5 weeks for LTBMCs
initiated with CD34+ HLA- DR- CD15- cells obtained on day 15. Cumulative
cellular production by LTBMCs initiated with day 15 CD34+ HLA-DR- CD15-
cells was statistically greater than that by day 0 LTBMCs (P = .031). These
same cultures produced CFU-GM for 6.3 weeks (day 0) versus 9 weeks (day
15).(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 82,
Issue 3,
pp. 784-791,
08/01/1993
Copyright © 1993 by The American Society of Hematology
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