The CXCR4 antagonist 4F-benzoyl-TN14003 stimulates the recovery of the bone marrow after transplantation

Leukemia. 2009 Aug;23(8):1378-88. doi: 10.1038/leu.2009.56. Epub 2009 Mar 26.

Abstract

Cytopenia represents a significant complication after chemotherapy, irradiation before bone marrow (BM) transplantation or as a therapy for cancer. The mechanisms that determine the pace of BM recovery are not fully understood. During the recovery phase after chemotherapy or irradiation, the signals for retention of white blood cells within the BM increase significantly. This leads to a delay in the release of WBC, which can be overcome by targeting the CXCR4 axis with the antagonist 4F-benzoyl-TN14003 (T140). The delay in the release of WBC is also accompanied by suppression in the production of progenitor cells and mature cells by the BM stroma. Administration of T140 to mice transplanted with BM cells stimulates the production of all types of progenitors and mature cells, and increases the exit of mature cells to the periphery. Moreover, addition of T140, but not AMD3100, to BM stromal cultures stimulates the production of mature cells and progenitors from all lineages. The unique ability of the CXCR4 antagonist, T140 to stimulate the production and exit of WBC cells may be used as a novel therapeutic approach to overcome cytopenia associated with treatments for cancer and BM transplantation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / drug effects*
  • Bone Marrow / radiation effects
  • Cell Division / drug effects
  • Coculture Techniques
  • Colony-Forming Units Assay
  • Cyclophosphamide / pharmacology
  • Drug Evaluation, Preclinical
  • Female
  • Graft Survival / drug effects
  • Hematopoietic Stem Cell Mobilization / methods
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Heterocyclic Compounds / pharmacology
  • Heterocyclic Compounds / therapeutic use
  • Integrin alpha4beta1 / biosynthesis
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neutropenia / drug therapy
  • Neutropenia / etiology
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • Radiation Chimera
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / biosynthesis
  • Receptors, CXCR4 / physiology
  • Recovery of Function / drug effects
  • Specific Pathogen-Free Organisms
  • Stromal Cells / physiology

Substances

  • 4-fluorobenzoyl-TN-14003
  • CXCR4 protein, mouse
  • Heterocyclic Compounds
  • Integrin alpha4beta1
  • Peptides
  • Receptors, CXCR4
  • Cyclophosphamide
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • plerixafor