Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells.

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Herbert KE, Walkley CR, Winkler IG, Hendy J, Olsen GH, Yuan YD, Chandraratna RA, Prince HM, Levesque JP, Purton LE

Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells.

Transplantation. 2007 Feb 27;83(4):375-84.

PubMed ID
17318068 [ View in PubMed
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Abstract

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.

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