In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells.
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)
Tong
J
J
Hematology-Oncology Section, Indiana University School of Medicine, Indianapolis 46202-5121.
Gordon
M S
MS
Srour
E F
EF
Cooper
R J
RJ
Orazi
A
A
McNiece
I
I
Hoffman
R
R
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001854:Bone Marrow Cells; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D006410:Hematopoiesis / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000008:administration & dosage*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D016256:Lewis X Antigen; D011994:Recombinant Proteins; D019089:Stem Cell Factor
D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D006684:HLA-DR Antigens; D016298:Hematopoietic Cell Growth Factors; D016256:Lewis X Antigen; D011994:Recombinant Proteins; D019089:Stem Cell Factor