Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was purposed to investigate the effect of rapamycin on proliferation, apoptosis, cell cycle progression and the regulation of chemokine receptor CXCR4 on RPMI8226 cells. Different concentrations of rapamycin were used to treat the multiple myeloma cell line RPMI8226 for different times. The proliferation of the cells was detected by MTT assay; the apoptosis rate and cell cycle were determined by flow cytometry (FCM); apoptosis of cells was observed by inverted microscopy; the cylin D1, CXCR4 and mTOR mRNA expressions were detected by RT-PCR or FQ-PCR after treating RPMI8226 cells with different concentrations of rapamycin. The results indicated that the rapamycin could inhibit the proliferation of RPMI8226 cells and induce their apoptosis. The cell cycle was arrested at the G(0)/G(1) phase. PCR results showed the down-regulation of mTOR, cyclin D1 and mTOR mRNA expressions after treating RPMI8226 cells with different concentrations of rapamycin for 24 hours. It is concluded that the rapamycin significantly inhibits the growth of RPMI8226 cells in a dose-and time-dependent mannes and induce cell apoptosis. Cell cycle arrests at the G(0)/G(1) phase, may be due to the down-regulation of the mTOR and cyclin D1 expressions. In additions, the down-regulation of CXCR4 mRNA expression is correlated with the reduction of adhesion between myeloma cells and stromal cells.
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PMID:[Effect of rapamycin on proliferation, apoptosis and regulation of chemokine receptor CXCR4 in RPMI8226 cells]. 1937 72

We investigated the modulation of CXCR4 expression by cytokines, dexamethasone, and hypoxia in myeloma cells in vitro. Tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1 (TGF-beta1), and vascular endothelial growth factor (VEGF) enhanced CXCR4 expression in RPMI8226 cells. In the myeloma cell lines examined and primary bone marrow (BM) CD138+ cells, dexamethasone enhanced CXCR4 expression both in the cytoplasm and on the cell surface, while downregulating SDF-1 expression and secretion in BM stromal cells. Incubation of cells under hypoxic conditions (1% O(2)) also induced upregulation of CXCR4 in the cytoplasm and on the cell surface and enhanced chemotaxis in response to stromal cell-derived factor-1 (SDF-1). Cell surface CXCR4 expression was more prominent in annexin V-positive apoptotic cells. Given the roles of the SDF-1/CXCR4 axis in the development and progression of myeloma, CXCR4-downregulating agents may enhance the antitumor effects of dexamethasone.
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PMID:Dexamethasone and hypoxia upregulate CXCR4 expression in myeloma cells. 1955 26

Plerixafor, a novel CXCR4 inhibitor, is effective in mobilizing PBSCs particularly when used in conjunction with G-CSF. In four cohorts, this pilot study explored the safety of plerixafor mobilization when incorporated into a conventional stem cell mobilization regimen of chemotherapy and G-CSF. Forty (26 multiple myeloma and 14 non-Hodgkin's lymphoma) patients were treated with plerixafor. Plerixafor was well tolerated and its addition to a chemo-mobilization regimen resulted in an increase in the peripheral blood CD34+ cells. The mean rate of increase in the peripheral blood CD34+ cells was 2.8 cells/microl/h pre- and 13.3 cells/microl/h post-plerixafor administration. Engraftment parameters were acceptable after myeloblative chemotherapy, with the median day for neutrophil and plt engraftment being day 11 (range 8-20 days) and day 13 (range 7-77 days), respectively. The data obtained from the analysis of the cohorts suggest that plerixafor can safely be added to chemotherapy-based mobilization regimens and may accelerate the rate of increase in CD34+ cells on the second day of apheresis. Further studies are warranted to evaluate the effect of plerixafor in combination with chemomobilization on stem cell mobilization and collection on the first and subsequent days of apheresis, and its impact on resource utilization.
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PMID:Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization. 1948 60

To evaluate nuclear factor-kappaB (NF-kappaB) activity in primary myeloma cells from myeloma patients, we confirmed that the expression levels of CD54 showed a good correlation with the levels of DNA binding activity for NF-kappaB in human myeloma cell lines, and thus analyzed the expression levels of CD54 on CD38(++) plasma cell fractions as one of NF-kappaB activity. Primary myeloma cells unexpectedly showed constitutively lower expressions of CD54 than normal bone marrow (BM) plasma cells. Furthermore, the expression levels of CD54 on these plasma cells showed a significant correlation with the plasma levels of CXCL12 stromal cell-derived factor-1alpha (SDF-1alpha) in their BM aspirates, and the expressions of CXCR4, the receptor for CXCL12, decreased on primary myeloma cells compared with normal BM plasma cells. It was also confirmed that the addition of CXCL12 to the in vitro culture significantly induced the up-regulation of CD54 expression in primary myeloma cells. In addition, myeloma cells with lower expressions of CD54 were more unstable in the in vitro culture, resulting in a marked reduction of the viable cell number. In the immunohistochemical analysis of BM aspirates, myeloma cells with lower CD54 expression resided in the perivascular regions. Therefore, these data suggest that primary myeloma cells exhibit constitutively lower CD54 that might be partially regulated by CXCL12, and their localizations in the BM may be associated with the expression levels of CD54.
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PMID:Constitutively lower expressions of CD54 on primary myeloma cells and their different localizations in bone marrow. 1950 Jan 34

Plerixafor is a selective antagonist of CXCR4 used for mobilization of hematopoietic stem cells (HSCs) for autologous stem cell transplantation (SCT) in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This Phase 1 open-label study in healthy subjects was conducted to evaluate the pharmacokinetic characteristics of plerixafor in subjects with renal impairment. All subjects received a single 0.24 mg/kg subcutaneous dose of plerixafor. Subjects were stratified into 4 cohorts based on creatinine clearance determined from a 24-hour urine collection: control (>90 mL/min), mild renal impairment (51-80 mL/min), moderate renal impairment (31-50 mL/min), and severe renal impairment (<31 mL/min, not requiring dialysis). Eleven female subjects (48%) and 12 male subjects (52%), ranging in age from 35 to 73 years, were enrolled. Plerixafor clearance was reduced in subjects with renal impairment and was positively correlated with creatinine clearance. The mean area under the concentration- versus-time curve from time 0 to 24 hours postdose of plerixafor in subjects with mild, moderate, and severe renal impairment was 7%, 32%, and 39% higher, respectively, than that in subjects with normal renal function. Renal impairment had no effect on maximal plasma concentrations. The safety profile was similar among subjects with renal impairment and controls. No renal impairment-related trends in the incidence of adverse events were apparent. A plerixaflor dose reduction to 160 microg/kg in patients with a creatinine clearance value <or= 50 mL/min is expected to result in exposure similar to that in patients with normal to mildly impaired renal function.
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PMID:A pharmacokinetic study of plerixafor in subjects with varying degrees of renal impairment. 1974 93

Plerixafor is a novel small molecule that inhibits CXCR4 binding to SDF-1, an interaction that is a principal regulator of hematopoietic stem cell trafficking. Phase I studies demonstrated that a single plerixafor hydrochloride dose results in a marked increase in white blood cell count and circulating CD34(+) stem cells. Subsequent single-arm and randomized clinical trials have established the efficacy of plerixafor for autologous stem cell mobilization, both combined with granulocyte colony-stimulating factor (G-CSF) and as a single agent. In December 2008 the FDA approved plerixafor in combination with G-CSF for autologous stem cell mobilization in patients with non-Hodgkin lymphoma or multiple myeloma. Plerixafor is also effective for stem cell mobilization in patients with Hodgkin lymphoma and in those who have failed a prior cytokine or chemotherapy mobilization. Preliminary studies of plerixafor in sibling donors demonstrate its efficacy for allogeneic stem cell mobilization, without any observed increase in graft failure or graft versus host disease. This review will summarize clinical trials, current use for autologous stem cell mobilization and future directions for plerixafor.
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PMID:Plerixafor hydrochloride: a novel agent for the mobilization of peripheral blood stem cells. 1983 27

Rapid and durable recovery of hematopoietic function after hematopoietic stem cell transplantation (HSCT) requires the infusion of a sufficient number of hematopoietic stem cells (HSC). Granulocyte colony-stimulating factor (G-CSF), either alone or with chemotherapy, has been the traditional backbone of regimens used to mobilize HSC. Plerixafor (previously known as AMD3100), a selective antagonist of CXCR4, has recently been approved for autologous HSC mobilization in combination with G-CSF. The current study assessed the safety and efficacy of plerixafor as a single agent when given subcutaneously and followed by apheresis 6 hours later for the mobilization of HSC for transplantation in 9 patients with multiple myeloma (MM). All patients mobilized enough cells for at least 1 transplant, and demonstrated prompt recovery of hematopoietic function. Median time to engraftment was 10.5 days for neutrophils and 21 days for platelets. Significant adverse events were not observed. Recovery of peripheral blood cell counts was durable in all surviving patients. Despite these successes, mobilization with plerixafor alone was modest. However, in clinical circumstances where G-CSF or chemotherapy based-mobilization should not be used, mobilization with plerixafor alone may be required and effective. Further research into single agent use should focus on alternate route of administration as well as adjustment of the timing of the apheresis to improve cell HSC yield.
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PMID:Plerixafor (Mozobil) alone to mobilize hematopoietic stem cells from multiple myeloma patients for autologous transplantation. 2006 38

It has been well documented that bone marrow stromal cells (BMSCs) of multiple myeloma patients play a pivotal role in supporting the growth of mature myeloma cells. With evolving concepts concerning the presence of myeloma stem (initiating) cells, we aimed this investigation to specifically address the supportive role of BMSCs for myeloma stem cell growth in vitro and in vivo. BMSC lines were derived from myeloma or control patients (myeloma or control BMSCs). Myeloma stem cells of the RPMI 8226 myeloma cell line were recognized through the identification of "side populations" (SP) with Hoechst dye staining. SP cells formed more colonies when grown on myeloma BMSC than on control BMSC. Additionally, higher percentages of SP cells were observed when grown on myeloma BMSCs than on control BMSCs. In the mouse model, SP cells inoculated with myeloma BMSCs grew faster than those inoculated with control BMSCs. Of note, SP cells demonstrated an increased expression of CD184 (CXCR4) compared with non-SP cells. The expression of CD184 in SP cells was further increased when they were cultured with myeloma BMSCs. CD184(+) SP cells formed more colonies than CD184(-) SP cells. Treatment with AMD 3100, an inhibitor of CD184, reduced colony formation by CD184(+) SP cells when co-cultured with myeloma BMSCs. This was associated with the decreased activation of ERK, a downstream target of activated CD184, in myeloma cells. These findings indicate that the myeloma BMSCs create a microenvironment supportive of myeloma stem cells via, at least partially, the CXCR4 signaling pathway.
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PMID:Bone marrow stromal cells from myeloma patients support the growth of myeloma stem cells. 2012 56

Pharmacological manipulation of CXCR4 has proven clinically useful for mobilization of stem and progenitor cells and in several preclinical models of disease. It is a key component in the localization of leukocytes and stem cells. For patients with multiple myeloma and non-Hodgkin's Lymphoma, treatment with plerixafor, an inhibitor of CXCL12 binding to CXCR4, plus G-CSF mobilizes stem cells for autologous transplantation to a greater degree than the treatment with G-CSF alone, and in some cases when patients could not be mobilized with cytokines, chemotherapy, or the combination. Stem cells from healthy donors mobilized with single agent plerixafor have been used for allogeneic transplantation in acute myelogenous leukemia (AML) patients, although this is still in the early phase of clinical development. Plerixafor is also undergoing evaluation to mobilize tumor cells in patients with AML and chronic lymphocytic leukemia (CLL) to enhance the effectiveness of chemotherapy regimens. Plerixafor's effect on neutrophils may also restore circulating neutrophil counts to normal levels in patients with chronic neutropenias such as in WHIMs syndrome. Other areas where inhibition of CXCR4 may be useful based upon preclinical or clinical data include peripheral vascular disease, autoimmune diseases such as rheumatoid arthritis, pulmonary inflammation, and HIV.
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PMID:CXCR4 in clinical hematology. 2039 73

Multiple myeloma is an incurable hematological malignancy of terminally differentiated immunoglobulin-producing plasma cells. As a common presentation of the disease, the malignant plasma cells accumulate and proliferate in the bone marrow, where they disrupt normal hematopoiesis and bone physiology. Multiple myeloma cells and the bone marrow microenvironment are linked by a composite network of interactions mediated by soluble factors and adhesion molecules. Integrins and syndecan-1/CD138 are the principal multiple myeloma receptor systems of extracellular matrix components, as well as of surface molecules of stromal cells. CD44 and RHAMM are the major hyaluronan receptors of multiple myeloma cells. The SDF-1/CXCR4 axis is a key factor in the homing of multiple myeloma cells to the bone marrow. The levels of expression and activity of these adhesion molecules are controlled by cytoplasmic operating mechanisms, as well as by extracellular factors including enzymes, growth factors and microenvironmental conditions. Several signaling responses are activated by adhesive interactions of multiple myeloma cells, and their outcomes affect the survival, proliferation and migration of these cells, and in many cases generate a drug-resistant phenotype. Hence, the adhesion systems of multiple myeloma cells are attractive potential therapeutic targets. Several approaches are being developed to disrupt the activities of adhesion molecules in multiple myeloma cells, including small antagonist molecules, direct targeting by immunoconjugates, stimulation of immune responses against these molecules, and signal transduction inhibitors. These potential novel therapeutics may be incorporated into current treatment schemes, or directed against minimal residual malignant cells during remission.
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PMID:Adhesion molecules--The lifelines of multiple myeloma cells. 2041 79


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