UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CXC chemokine SDF-1 has been characterized as a T-cell chemoattractant both in vitro and in vivo. To determine whether SDF-1 expression within tumors can influence tumor growth, we transfected an expression vector pCI-SDF-1 for SDF-1 into J558 myeloma cells and tested their ability to form tumors in BALB/c. Production of biologically active SDF-1 (1.2 ng/mL) was detected in the culture supernatants of cells transfected with the expression vector pCI-SDF-1. J558 cells gave rise to a 100% tumor incidence, whereas SDF-1-expressing J558/SDF-1 tumors invariably regressed in BALB/c mice and became infiltrated with CD4(+) and CD8(+) T cells. Regression of the J558/SDF-1 tumors was dependent on both CD4(+) and CD8(+) T-cells. Our data also indicate that TIT cells containing both CD4(+) and CD8(+) T-cells within J558/SDF-1 tumors express the SDF-1 receptor CXCR4, and that SDF-1 specifically chemoattracts these cells in vitro. Furthermore, immunization of mice with engineered J558/SDF-1 cells elicited the most potent protective immunity against 0.5 x 10(6) cells J558 tumor challenge in vivo, compared to immunization with the J558 alone, and this antitumor immunity mediated by J558/SDF-1 tumor cell vaccination in vivo appeared to be dependent on CD8(+) CTL. Thus, SDF-1 has natural adjuvant activities that may augment antitumor responses through their effects on T-cells and thereby could be important in gene transfer immunotherapies for some cancers.
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PMID:Vaccine of engineered tumor cells secreting stromal cell-derived factor-1 induces T-cell dependent antitumor responses. 1611 88

The bicyclam AMD3100 (originally called JM3100), in which the two cyclam rings are tethered by an aromatic bridge, emanated from JM2763, where the two cyclam moieties are tethered by an aliphatic linker - JM2763 in turn originated from JM1657, where the cyclam rings are directly linked to one another via a C-C bridge, and which was identified as an impurity, showing anti-HIV activity, in a commercial cyclam preparation. AMD3100 proved very effective against HIV-1 and HIV-2, inhibiting virus replication within the nM range, without toxicity for the host cells at concentrations that were > 100,000-fold higher than those required to inhibit HIV replication. The anti-HIV activity of AMD3100 appeared to be confined to the T-lymphotropic (X4) HIV strains, i.e. those strains that use the CXCR4 receptor to enter their target cells, and AMD3100 as of today still stands as one of the most potent and selective CXCR4 antagonists ever discovered. Hence, AMD3100 was found to interfere with a number of (patho)physiological processes which depend on the interaction of CXCR4 with its natural ligand, stromal derived factor (SDF-1) and which play an important role in rheumatoid, allergic and malignant diseases. AMD3100 has been shown to mobilize CD34+ stem cells from the bone marrow into the bloodstream and has also been shown to augment migration of bone marrow-derived endothelial progenitor cells into sites of neovascularization after myocardial infarction. Currently, AMD3100 is actively pursued as a stem cell mobilizer for transplantation in patients with multiple myeloma and non-Hodgkin's lymphoma.
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PMID:Potential clinical applications of the CXCR4 antagonist bicyclam AMD3100. 1617 23

G-CSF mobilization of hematopoietic progenitor cells (HPCs) is mediated through enzyme release from maturing myeloid cells, leading to digestion of adhesion molecules, trophic chemokines and their receptors, and the extracellular matrix. HPCs traffic to and are retained in the marrow through the trophic effects of the chemokine SDF-1alpha/CXCL12 binding to its receptor, CXCR4. AMD3100 reversibly inhibits SDF-1alpha/CXCR4 binding, and AMD3100 administration mobilizes CD34+ cells into the circulation. AMD3100 has been tested in several clinical trials which demonstrate that it improves the number of CD34+ cells mobilized including patients failing to mobilize with G-CSF alone. Engraftment of AMD3100-mobilized cells is prompt and durable. Toxicities are mild and infrequent. Lymphoma and myeloma cells do not appear to be mobilized. AMD3100 appears to be a promising agent for HPC mobilization.
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PMID:Role of CXCR4 chemokine receptor blockade using AMD3100 for mobilization of autologous hematopoietic progenitor cells. 1626 59

The chemokine receptor CXCR4 is widely expressed on different cell types, is involved in leukocyte chemotaxis, and is a co-receptor for HIV. AMD3100 has been shown to be a CXCR4 receptor antagonist, and to block HIV infection of T-tropic, X4-using, virus in vitro and in vivo. AMD3100 is an effective mobilizer of hematopoietic stem cells and is being investigated in clinical trials in multiple myeloma and non-Hodgkins lymphoma patients. Using the CCRF-CEM T-cell line that constitutively expresses CXCR4 we confirmed that AMD3100 was an antagonist of SDF-1/CXCL12 ligand binding (IC50=651+/-37 nM). We have also shown that AMD3100 inhibits SDF-1 mediated GTP-binding (IC50=27+/-2.2 nM), SDF-1 mediated calcium flux (IC50=572+/-190 nM), and SDF-1 stimulated chemotaxis (IC50=51+/-17 nM). AMD3100 did not inhibit calcium flux against cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7 when stimulated with their cognate ligands, nor did it inhibit receptor binding of LTB4. AMD3100 did not, on its own, induce a calcium flux in the CCRF-CEM cells, which express multiple GPCRs including CXCR4, CCR4 and CCR7. Furthermore, AMD3100 neither stimulated GTP-binding, an assay for GPCR activation, in CEM cell membranes; nor chemotaxis of CCRF-CEM cells. These data therefore demonstrate that AMD3100 is a specific antagonist of CXCR4, is not cross-reactive with other chemokine receptors, and is not an agonist of CXCR4.
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PMID:Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. 1681 9

Hematopoietic stem cell transplantation (HSCT) has become the standard of care for the treatment of many hematologic malignancies, chemotherapy sensitive relapsed acute leukemias or lymphomas, multiple myeloma; and for some non-malignant diseases such as aplastic anemia and immunodeficient states. The hematopoietic stem cell (HSC) resides in the bone marrow (BM). A number of chemokines and cytokines have been shown in vivo and in clinical trials to enhance trafficking of HSC into the peripheral blood. This process, termed stem cell mobilization, results in the collection of HSC via apheresis for both autologous and allogeneic transplantation. Enhanced understanding of HSC biology, processes involved in HSC microenvironmental interactions and the critical ligands, receptors and cellular proteases involved in HSC homing and mobilization, with an emphasis on G-CSF induced HSC mobilization, form the basis of this review. We will describe the key features and dynamic processes involved in HSC mobilization and focus on the key ligand-receptor pairs including CXCR4/SDF1, VLA4/VCAM1, CD62L/PSGL, CD44/HA, and Kit/KL. In addition we will describe food and drug administration (FDA) approved and agents currently in clinical development for enhancing HSC mobilization and transplantation outcomes.
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PMID:Cytokines and hematopoietic stem cell mobilization. 1688 4

The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the P13K and ERK/ MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.
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PMID:Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. 1711 15

Plerixafor [Mozobil, AMD 3100, JM 3100, SDZ SID 791] is a bicyclam derivative that acts as a stem cell mobiliser by blocking the CXCR4 chemokine receptor. Plerixafor was synthesised by Johnson Matthey (AnorMED) in collaboration with the Rega Institute of Leuven, Belgium. Plerixafor is in phase III clinical trials in stem cell transplantation among cancer patients. Plerixafor blocks CXCR4, which triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. These cells can then be collected and used in stem cell transplant procedures. Plerixafor had been available for partnering in Europe. However, decisions concerning partnering arrangements were deferred by AnorMED until top-line clinical data became available (expected in 2007). In November 2006, Genzyme Corporation completed its acquisition of AnorMED. Genzyme intends to commercialise plerixafor in >50 countries throughout the world using its existing transplant business. Evotec OAI was selected by AnorMED to support it in the chemical development of plerixafor. Evotec OAI will use EVOdevelop, its integrated chemical and pharmaceutical development platform, to complete the full validation of the process to plerixafor, including process research and development, cGMP manufacturing and analytical work. Evotec OAI will also be responsible for producing the relevant Chemical Manufacturing Control (CMC) documentation for regulatory filings. Top line results from the phase III studies are expected in the second quarter of 2007 and, assuming these are successful, the marketing submissions are planned for the US in 2007 (launch in 2008), and for Canada and Europe in 2008. Plerixafor has orphan drug status for stem cell transplantation in cancer patients in the US and the EU. AnorMED (now Genzyme) decided to pursue a full Marketing Authorisation Application (MAA) in Europe for plerixafor in stem cell transplant. Previously, the company had been planning on filing a CMA (Conditional Marketing Authorisation) in this region. The change in strategy requires additional phase II trials in the five major EU markets. Multicentre phase II trials with plerixafor have begun in Canada and Germany in approximately 50 patients with non-Hodgkin's lymphoma and multiple myeloma (studies EU21 and C201). Enrolment has been completed in a US-based, multicentre, phase II trial (study 2105) of plerixafor plus G-CSF in patients with multiple myeloma and non-Hodgkin's lymphoma. This study is designed to optimise the administration schedule of this combination therapy regimen. Plerixafor has completed a phase II study (study 2104) in multiple myeloma and NHL patients in combination with chemotherapy. A US-based phase II pilot study (study 2108) with plerixafor as a single mobilising agent in multiple myeloma patients undergoing stem cell transplant is underway. Another US-based phase II pilot study (study 2106) is evaluating plerixafor in combination with the standard mobilisation regimen, G-CSF, in patients with Hodgkin's disease undergoing stem cell transplant. AnorMED completed a phase II study (study 2101) evaluating the potential of plerixafor in combination with G-CSF as a therapy for stem cell transplantation compared to G-CSF therapy alone. The study involved patients with multiple myeloma and patients with NHL. Results indicated that the combination regimen was significantly superior to G-CSF treatment alone in stem cell mobilisation. Further trials are planned for plerixafor, to expand its use in transplant and in other indications including one to investigate the potential of plerixafor to improve the effectiveness of chemotherapy in patients with leukaemia. Phase I trials have been completed.
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PMID:Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791. 1732 9

AMD3100, a competitive antagonist of CXCR-4, disrupts the binding of its ligand, stromal cell-derived factor-1 (SDF-1), and facilitates stem cell mobilisation in patients with haematological malignancies. This study investigated the differential kinetics of CXCR-4 and adhesion molecule expression and their impact on stem cell yield during mobilisation with granulocyte-colony stimulating factor (G-CSF) (days 1-4) followed by AMD3100 in 10 patients with multiple myeloma. A four-colour flow cytometry-based determination of CXCR-4, VLA-4, L-selectin, PECAM, LFA-1 and CD44 expression on CD34+ cells and measurement of SDF-1 concentration were performed at different time points. After G-CSF alone, CXCR-4 expression on patients' blood and marrow CD34+ cells was significantly lower than in the healthy controls (p < 0.001), but allowed no prediction of stem cell yield. Except in the single poorly mobilising patient, AMD3100 led to a further significant decrease of CXCR4 (p = 0.001), which inversely correlated with the CD34+ counts in the blood (p = 0.005). SDF-1 level in patients' marrow was positively correlated with CXCR-4 expression on CD34+ cells (p = 0.011). It is interesting to note that the expression of adhesion molecules remained unaffected by AMD3100 administration. Further studies will define the possible prognostic role of AMD3100 mediated changes in CXCR-4 expression for the prediction of stem cell yield attainable with this new mobilisation regimen.
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PMID:Kinetics of CXCR-4 and adhesion molecule expression during autologous stem cell mobilisation with G-CSF plus AMD3100 in patients with multiple myeloma. 1743 11

Chemokines and their receptors play a pivotal role in the regulation of B-lymphocyte trafficking. This study was aimed at investigating the pattern of chemokine receptor expression, including CCR1 to CCR3, CCR5 to CCR7, CXCR1 to CXCR5, and the migration ability of multiple myeloma (MM) plasma cells (PC). PC were recovered from the bone marrow (BM) of 29 MM patients, extramedullary sites of 10 patients and the BM of five controls. Flow cytometry analysis showed that the receptors mainly expressed on malignant BM PC were represented by CXCR4 (70% of patients), CCR1 (25%), CCR2 (25%), CCR5 (17%) and CXCR3 (20%), while other receptors were commonly lacking. The analysis performed on extramedullary (peripheral blood and pleural effusion) malignant PC demonstrated that the most represented receptors were CXCR4 (100%), CCR2 (66%) and CXCR1 (60%). The migratory capability of malignant PC at resting conditions identified three groups of patients with different migration (low, intermediate and high). As CXCR4 was the relevant chemokine receptor expressed by MM PC, its ligand CXCL12 induced their migration. These data suggest that malignant PC from MM display different chemokine receptor profiles and that CXCR4 is fully functional and might play a role in the spreading of the disease.
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PMID:Multiple myeloma plasma cells show different chemokine receptor profiles at sites of disease activity. 1768 53

As patients with multiple myeloma (MM) have a variable clinical course, predictive markers would help determine the appropriate treatment strategy. Clinical staging is commonly used to predict outcome, but tumour marker expression and the underlying genetic changes are increasingly used to assess the biological aggressiveness of the disease. Recent studies have demonstrated the utility of immunohistochemistry in detecting prognostic markers, including fibroblast growth factor receptor 3, cyclin D1, c-maf and p53, which have been associated with various genetic aberrations, including t(4;14), t(11;14), t(14;16) and del(17p). While t(4;14), t(14;16) and del (17p) have been documented to confer a poor prognosis, t(11;14) appears to be a neutral or even favourable factor in some studies. CD56, CD33, CD20 and CXCR4 are promising surface markers due to their roles in MM progression, but further studies of larger cohorts are necessary to assess their prognostic relevance. In this review, the biological function and clinical relevance of the main prognostic markers in MM is discussed, and also the role of immunohistochemistry in the stratification of patients into appropriate risk categories.
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PMID:Genomic aberrations and immunohistochemical markers as prognostic indicators in multiple myeloma. 1807 70

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