Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist.
Stromal cell-derived factor 1 (SDF1/CXCL12) and its cognate receptor, CXCR4, play key regulatory roles in CD34+ cell trafficking. We investigated whether AMD3100, a selective CXCR4 antagonist, could mobilize hematopoietic progenitor cells from marrow to peripheral blood in healthy human volunteers. Initially, 10 persons each received a single dose of AMD3100 (80 microsubcutaneously), which induced rapid, generalized leukocytosis associated with an increase in peripheral blood CD34+ cells, representing pluripotent hematopoietic progenitors by in vitro colony-forming unit assays, from 3.8 +/- 0.5/microL to 20.7 +/- 3.5/microL at 6 hours. Subsequent dose-response studies showed a maximum increase in circulating CD34+ cells from 2.6 +/- 0.3/microL to 40.4 +/- 3.4/microL at 9 hours after 240 micro/kg AMD3100. Serial administration of AMD3100 (80 microg/kg/d for 3 days) resulted in consistent, reversible increases in peripheral blood CD34+ cells. AMD3100 was well tolerated and caused only mild, transient toxicity. These findings suggest potential clinical application of AMD3100 for CD34+ cell mobilization and collection for hematopoietic stem cell transplantation.
Liles
W Conrad
WC
Department of Medicine, University of Washington, HSB AA-522, Box 356422, Seattle, WA 98195. dcdale@u.washington.edu
Broxmeyer
Hal E
HE
Rodger
Elin
E
Wood
Brent
B
Hübel
Kai
K
Cooper
Scott
S
Hangoc
Giao
G
Bridger
Gary J
GJ
Henson
Geoffrey W
GW
Calandra
Gary
G
Dale
David C
DC
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D018952:Antigens, CD34 / Q000096:biosynthesis; D001596:Benzylamines; D000080027:Cyclams; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008297:Male; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013997:Time Factors
D019380:Anti-HIV Agents; D018952:Antigens, CD34; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor