Abstract:866
Background:
Stem cells are retained in the bone marrow via the trophic effects of the binding of chemokine stromal cell-derived factor-1α (SDF-1α) to its receptor, CXC chemokine receptor 4 (CXCR4). TG-0054 inhibits SDF-1α/CXCR4 binding and therefore mobilizes stem cells into peripheral blood. Animal studies in mice showed rapid and effective mobilization of CD34+ hematopoietic stem cells (HSCs) and CD133+ endothelial progenitor cells (EPCs) into periphera… Show more
“…Phase I clinical trials revealed that single-dose administration of the antagonist more than increased the number of circulating stem cells to the numbers required for a successful transplant. 213 Phase 1 results also indicated that TG-0054 may be given as a monotherapy in contrast to 36 that is given with granulocyte macrophage colony stimulating factor (GM-CSF). Currently the antagonist is undergoing several phase II clinical trials for the treatment of multiple myeloma and non-Hodgkin's lymphoma.…”
Section: Journal Of Medicinal Chemistrymentioning
confidence: 99%
“…Receptor binding studies revealed potencies for CXCR4 ranging from 4 to 100 nM, and a prototypical structure is shown ( 37 , Figure ). Phase I clinical trials revealed that single-dose administration of the antagonist more than increased the number of circulating stem cells to the numbers required for a successful transplant . Phase 1 results also indicated that TG-0054 may be given as a monotherapy in contrast to 36 that is given with granulocyte macrophage colony stimulating factor (GM-CSF).…”
“…Phase I clinical trials revealed that single-dose administration of the antagonist more than increased the number of circulating stem cells to the numbers required for a successful transplant. 213 Phase 1 results also indicated that TG-0054 may be given as a monotherapy in contrast to 36 that is given with granulocyte macrophage colony stimulating factor (GM-CSF). Currently the antagonist is undergoing several phase II clinical trials for the treatment of multiple myeloma and non-Hodgkin's lymphoma.…”
Section: Journal Of Medicinal Chemistrymentioning
confidence: 99%
“…Receptor binding studies revealed potencies for CXCR4 ranging from 4 to 100 nM, and a prototypical structure is shown ( 37 , Figure ). Phase I clinical trials revealed that single-dose administration of the antagonist more than increased the number of circulating stem cells to the numbers required for a successful transplant . Phase 1 results also indicated that TG-0054 may be given as a monotherapy in contrast to 36 that is given with granulocyte macrophage colony stimulating factor (GM-CSF).…”
“…Examining these varied studies, an extension of plerixafor indications is to be expected in the coming years, as are new pharmacological alternatives. Indeed, new compounds targeting CXCR4 are in development: small molecules (TG-0054 [60,61,62]) such as plerixafor, but also peptides (BL-8040 [63], (BK)T140 [64], POL6326 [65], LY2510924 [66]), or oligonucleotides (NOX-A12 [67]). All have already been tested in humans as part of phase I or early phase II clinical trials.…”
Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for several malignant and non-malignant diseases at the cost of serious treatment-related toxicities (TRTs). Recent research on extending the benefits of HSCT to more patients and indications has focused on limiting TRTs and improving immunological effects following proper mobilization and engraftment. Increasing numbers of studies report associations between HSCT outcomes and the expression or the manipulation of G protein-coupled receptors (GPCRs). This large family of cell surface receptors is involved in various human diseases. With ever-better knowledge of their crystal structures and signaling dynamics, GPCRs are already the targets for one third of the current therapeutic arsenal. The present paper assesses the current status of animal and human research on GPCRs in the context of selected HSCT outcomes via a systematized survey and analysis of the literature.
“…To ensure that TG-0054, which was shown to mobilize HSCs in mice and humans (11, 22), was effective in mobilizing CXCR4+ stem cells in minipigs, we analyzed PB cell components after TG-0054 treatment (two intravenous doses of 2.85 mg/kg TG-0054 of 72 h apart). TG-0054 increased PB white blood cell (WBC) counts, which peaked at 0.5 and 1 h after the first dose and the second dose, respectively (Fig.…”
Interaction between chemokine stromal cell-derived factor 1 and the CXC chemokine receptor 4 (CXCR4) governs the sequestration and mobilization of bone marrow stem cells. We investigated the therapeutic potential of TG-0054, a novel CXCR4 antagonist, in attenuating cardiac dysfunction after myocardial infarction (MI). In miniature pigs (minipigs), TG-0054 mobilized CD34(+)CXCR4(+), CD133(+)CXCR4(+), and CD271(+)CXCR4(+) cells into peripheral circulation. After isolation and expansion, TG-0054-mobilized CD271(+) cells were proved to be mesenchymal stem cells (designated CD271-MSCs) since they had trilineage differentiation potential, surface markers of MSCs, and immunosuppressive effects on allogeneic lymphocyte proliferation. MI was induced in 22 minipigs using balloon occlusion of the left anterior descending coronary artery, followed by intravenous injections of 2.85 mg/kg of TG-0054 or saline at 3 days and 7 days post-MI. Serial MRI analyses revealed that TG-0054 treatment prevented left ventricular (LV) dysfunction at 12 weeks after MI (change of LV ejection fraction from baseline, -1.0 ± 6.2% in the TG-0054 group versus -7.9 ± 5.8% in the controls). The preserved cardiac function was accompanied by a significant decrease in the myocardial expression of TNF-α, IL-1β, and IL-6 at 7 days post-MI. Moreover, the plasma levels of TNF-α, IL-1β, and IL-6 were persistently suppressed by the TG-0054 treatment. Infusion of TG-0054-mobilized CD271-MSCs reduced both myocardial and plasma cytokine levels in a pattern, which is temporally correlated with TG-0054 treatment. This study demonstrated that TG-0054 improves the impaired LV contractility following MI, at least in part, by mobilizing MSCs to attenuate the postinfarction inflammation. This insight may facilitate exploring novel stem cell-based therapy for treating post-MI heart failure.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.