Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12
| Autor: | Werner Purschke, Axel Vater, D Vossmeyer, Stefan Vonhoff, Sven Klussmann, M Lioznov, Klaus Buchner, Christian Maasch, Frank Schwoebel, K Hübel, M Humphrey, Anna Kruschinski, Stefan Zöllner, N Kröger, J Sahlmann, Frank Fliegert |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Stromal cell Adolescent Oligonucleotides Pharmacology CXCR4 Leukocyte Count Mice Young Adult Leukocytes Medicine Animals Humans Pharmacology (medical) Progenitor cell Receptor Hematopoietic Stem Cell Mobilization Mobilization Dose-Response Relationship Drug business.industry Middle Aged Hematopoietic Stem Cells Chemokine CXCL12 Haematopoiesis Cancer cell Models Animal Macaca Female business |
| Zdroj: | Clinical pharmacology and therapeutics. 94(1) |
| ISSN: | 1532-6535 |
| Popis: | NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12 (stromal cell–derived factor-1, SDF-1) with high affinity thereby inhibiting CXCL12 signaling on both its receptors, CXCR4 and CXCR7. In animals, NOX-A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX-A12 had a benign safety profile and also dose-dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half-life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose-dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX-A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long-lasting mobilization and chemosensitization of hematological cancer cells. Clinical Pharmacology & Therapeutics (2013); 94 1, 150–157. doi:10.1038/clpt.2013.58 |
| Databáze: | OpenAIRE |
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