Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells.
BACKGROUND
Failure to mobilize adequate numbers of hematopoietic stem and progenitor cells (HSPC) is an important clinical problem. Since bone marrow (BM) neutrophils play a central role in HSPC mobilization, we hypothesized that granulocyte colony-stimulating factor (G-CSF)-mediated mobilization would be enhanced by further expanding the size of the BM granulocyte pool.


METHODS
We tested the potential of the retinoic acid receptor alpha (RARalpha) specific agonist VTP195183, and the pan-RAR agonist all-trans retinoic acid (ATRA), to enhance G-CSF-mediated mobilization of HSPC, in two mouse strains.


RESULTS
Pretreatment of mice with VTP195183 significantly increased the number of leukocytes, colony-forming cells, and early engrafting hematopoietic stem cells (HSC) mobilized in the blood in response to G-CSF. In contrast, ATRA had only a marginal effect on G-CSF-induced mobilization. HSPC mobilization synergy between VTP195183 and G-CSF occurred only when mice were preconditioned with VTP195183 prior to G-CSF. This preconditioning was shown to increase the numbers of granulocyte/macrophage progenitors in the BM. Treatment with VTP195183 and G-CSF was accompanied by enhanced levels of active neutrophil proteases in the BM extracellular fluid compared to G-CSF treatment alone.


CONCLUSIONS
VTP195183 treatment increases the numbers of immature granulocyte progenitors in BM and subsequently synergizes to enhance G-CSF-mediated mobilization of HSPC. These data demonstrate a novel approach to improve G-CSF-induced mobilization by accelerating granulocyte maturation in the BM. These findings are currently being tested in a clinical trial of VTP195183 plus G-CSF for mobilization of HSPC in human patients.
Herbert
Kirsten E
KE
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Walkley
Carl R
CR
Winkler
Ingrid G
IG
Hendy
Jean
J
Olsen
Gemma Haines
GH
Yuan
Yang-Dar
YD
Chandraratna
Roshantha A S
RA
Prince
H Miles
HM
Lévesque
Jean-Pierre
JP
Purton
Louise E
LE
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D016179:Granulocyte Colony-Stimulating Factor / Q000819:agonists* / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010447:Peptide Hydrolases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology
C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D006157:Guanosine Monophosphate; D010447:Peptide Hydrolases