Enhanced unique pattern of hematopoietic cell mobilization induced by the CXCR4 antagonist 4F-benzoyl-TN14003.
An increase in the number of stem cells in blood following mobilization is required to enhance engraftment after high-dose chemotherapy and improve transplantation outcome. Therefore, an approach that improves stem cell mobilization is essential. The interaction between CXCL12 and its receptor, CXCR4, is involved in the retention of stem cells in the bone marrow. Therefore, blocking CXCR4 may result in mobilization of hematopoietic progenitor and stem cells. We have found that the CXCR4 antagonist known as 4F-benzoyl-TN14003 (T-140) can induce mobilization of hematopoietic stem cells and progenitors within a few hours post-treatment in a dose-dependent manner. Furthermore, although T-140 can also increase the number of white blood cells (WBC) in blood, including monocytes, B cells, and T cells, it had no effect on mobilizing natural killer cells. T-140 was found to efficiently synergize with granulocyte colony-stimulating factor (G-CSF) in its ability to mobilize WBC and progenitors, as well as to induce a 660-fold increase in the number of erythroblasts in peripheral blood. Comparison between the CXCR4 antagonists T-140 and AMD3100 showed that T-140 with or without G-CSF was significantly more potent in its ability to mobilize hematopoietic stem cells and progenitors into blood. These results demonstrate that different CXCR4 antagonists may have different therapeutic potentials.
Abraham
Michal
M
Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, P.O. Box 12000, Jerusalem, 91120 Israel.
Biyder
Katia
K
Begin
Michal
M
Wald
Hanna
H
Weiss
Ido D
ID
Galun
Eithan
E
Nagler
Arnon
A
Peled
Amnon
A
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
C477728:4-fluorobenzoyl-TN-14003; C514936:CXCR4 protein, mouse; D010455:Peptides; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor