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)

Using a combination of GM-CSF, SCF, flk-2/flt-3 ligand, and IL-4, dendritic cells (DC) have been generated in vitro from the adherent fraction of mononuclear cells isolated from the blood of patients with MM. Analysis of cell yield showed no significant difference in DC yield (numbers or percentage of leucocytes) or total number of leucocytes generated in myeloma cultures compared to similar cultures prepared using mononuclear cells from the blood of healthy donors. The mean number of DC produced after 10d of culture were 8.19 x 10(5) and 9.87 x 10(5) cells (41% and 51% of all leucocytes) for the myeloma and normal cultures respectively. Flow cytometry investigation of phenotypic markers including CD1a, HLA-DR, CD80 (BB1/B7.1) and CD86 (B70/B7.2), and functional status (stimulatory potential in allogeneic mixed leucocyte reactions (MLR)) confirmed the generation of cells phenotypically identified as cultured DC. In addition, these cells were more effective than PBMC at stimulating allogeneic PBMC proliferation. These data demonstrate no difference between DC generated from patients with MM and healthy donors. This study was considered a prerequisite for future investigations directed towards developing effective immunotherapies for myeloma.
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PMID:Dendritic cells generated from the blood of patients with multiple myeloma are phenotypically and functionally identical to those similarly produced from healthy donors. 932 98

Recombinant human hematopoietic growth factors are widely used in the treatment of multiple myeloma (MM) especially due to the increasing role of autologous blood stem cell transplantation (ABSCT). We report a patient with MM in whom rapid extramedullary progression of disease was observed during stem cell mobilization with G-CSF. In 56-year-old man with relapsing IgG lambda MM myeloablative therapy with ABSCT was planned 2 years after diagnosis. G-CSF is increasing doses was used for mobilization. Ten days after the start of G-CSF therapy 2 extramedullary (subcutaneous) myeloma infiltrates appeared. For the second mobilization high dose cyclophosphamide and VP-16 with subsequent G-CSF was used. During the time of chemotherapy tumour infiltrates disappeared, however, after one week of G-CSF treatment rapid progression of disease with the formation of multiple extramedullary infiltrates occurred and the patient died in June 1996. Small pieces of subcutaneous tumour infiltrates were removed at autopsy and immediately frozen in liquid nitrogen. Using the panel of specific antibodies the expression of cytokine receptors (IL-1, 2, 3, 6, 7, 8, 10, SCF, gp130, G-CSF, GM-CSF, EPO) and Fas, Pgp and 24-34 kD multidrug resistance-associated protein were examined. However, no expression of cytokine receptors on tumor cells was found. On the contrary, high positivity of surface MDR associated proteins was observed.
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PMID:[Progression of multiple myeloma during treatment with recombinant G-CSF and absence of G-CSF and IL-6 cell surface receptors on malignant cells]. 992 31

As in other malignancies, peripheral blood progenitor cells (PBPC) have almost completely replaced bone marrow as the source of stem cells for autologous transplantation in multiple myeloma. PBPC collection could be optimized either by reducing contamination by the malignant clone or by increasing hematopoietic quality of the graft. Currently, the most promising technique for purifying the harvest is CD34 cell selection. Several pilot studies have shown the feasibility of this method in MM. However controlled studies are necessary to assess the clinical impact of CD34+ cell selection. In the IFM 94 study, CD34+ selection was optional. There was no significant difference between 50 patients receiving a CD34+ selected graft and 133 patients receiving non-selected PBPC, as regards duration of neutropenia, duration of thrombocytopenia, response rate, EFS or survival. Hematopoietic recovery after transplantation is related to the number of CD34+ cells infused. The optimal regimen for mobilizing the requested CD34+ yield is not yet known. We have completed a randomized study comparing the combination of SCF plus G-CSF and G-CSF alone after priming with cyclophosphamide 4 g/m2. The median number of leukaphereses to reach the target yield of 5x10(6) CD34+ cells/kg was 1 in the SCF group (N=55) versus 2 in the G-CSF group (N=47) (p=0.008). The median number of CD34+ cells collected in the first leukapheresis was 11. 6x10(6) in the SCF group versus 4x10(6) in the G-CSF group (p=0.003). These results are in line with those observed in other trials testing the combination of SCF and G-CSF to improve PBPC collection.
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PMID:Optimizing peripheral blood progenitor cell autologous transplantation in multiple myeloma. 1036

Dendritic cells (DCs) are extremely efficient antigen-presenting cells that are potent stimulators of both B and T cell immune responses. Although DCs are normally present in extremely small numbers in the circulation, recent advances in DC biology have made it possible to generate DCs in culture. DCs can be generated in vitro from various cellular sources including bone marrow, cord blood and peripheral blood. Although culture conditions are extremely diverse, the majority of protocols grow DCs in GM-CSF and either TNF-alpha and/or IL-4. The addition of other growth factors such as SCF and Flt-3 ligand can dramatically enhance DC recovery. It is important to appreciate that DC subsets have been identified. Thus, DC at different stages of maturation, based on phenotype and capacity to capture antigen, can be obtained depending on culture conditions. For clinical applications, DCs can be generated in serum-free media and cryopreserved for future clinical applications. The ability to obtain DCs in numbers suitable for manipulating immune responses has pushed DC-based immunotherapies into the spotlight for treatment of various malignancies, including multiple myeloma, a B cell malignancy that is presently incurable. Although high-dose chemotherapy and transplantation have improved complete remission rates and overall survival in myeloma, immunotherapeutic strategies are needed for the additional cytoreduction needed to achieve a cure. Because DCs specialize in antigen capture and are extremely potent at stimulating T cell responses, they are ideally suited for generating anti-myeloma T cell responses in vivo. Several studies have demonstrated that myeloma protein, also called idiotype (Id), is sufficiently immunogenic and can be used to generate in vivo T cell responses in myeloma patients. Clinical trials using Id-pulsed DCs as a vaccine to treat minimal residual disease or relapsed myeloma are currently underway. Feasibility studies indicate that antigen-pulsed autologous DCs can be used to elicit in vivo Id-specific T cell responses. Additional studies are needed to optimize current DC vaccination protocols and determine clinical benefits associated with this approach. It is hoped that, following conventional therapies, a combination of adoptive immunotherapeutic modalities such as DCs together with myeloma-specific T cells may lead to improved clinical responses in multiple myeloma, and ultimately lead to complete remission and cure.
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PMID:Dendritic cell biology and the application of dendritic cells to immunotherapy of multiple myeloma. 1071 54

To develop a model of early human adult B lymphopoiesis, we cultured CD34+CD38+CD10+ pro-B cells in contact with AFT024 stroma in X-VIVO10 media with 5% serum. The cytokines FLT3L + SCF + IL7 + IGF1 were added at day 0, IL4 + IL5 + IL6 + IL10 and soluble CD40 ligand at day 14, and Staph. aureus Cowan particles on day 21. Greater than 25-fold expansion of CD34+CD38+CD10+ cells was seen at 2 weeks, the majority being CD34-CD19+ pre-B cells. Differentiation to immature IgM+ B cells was seen at 3 weeks and mature IgD+ B cells at 4 weeks, with secretion of IgM into the media. Immature and mature B cells could also be generated from culture of CD34+CD10+CD19- and CD34+CD10+CD19+ cells under similar conditions. In conclusion, we have demonstrated in vitro differentiation of early pro-B cells, and possibly common lymphoid progenitor cells, to mature B cells. Additional stimuli, provided by T helper cells or dendritic cells for example, may be required for the generation of IgG+ B cells or plasma cells. However, our culture system should be a valuable tool to further investigate B cell biology and B cell malignancies such as multiple myeloma and lymphoma.
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PMID:A novel in vitro model of early human adult B lymphopoiesis that allows proliferation of pro-B cells and differentiation to mature B lymphocytes. 1099 8

Patients (n = 69) with multiple myeloma undergoing peripheral blood stem cell collection (PBSC) were treated with cyclophosphamide and a combination of recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) and recombinant methionyl human stem cell factor (r-metHuSCF, ancestim). The objectives of this study were to determine: (1) The proportion of patients reaching a target yield of >or=5 x 10(6) CD34(+) cells/kg in one or two successive large-volume (20 liter) leukapheresis procedures; (2) the optimal collection time for leukapheresis; (3) mobilization kinetics of CD34(+) subsets in response to G-CSF/SCF. All patients were mobilized with cyclophosphamide (2.5 g/m(2)) on day 0 followed by filgrastim (10 microg/kg ) plus ancestim (20 microg/kg) commencing day 1 and continuing to day 11 or 12. Of the 65 evaluable patients, 57 were considered not heavily pretreated and 96.5% obtained a target of >or=5 x 10(6)/kg in one collection. The median CD34(+) cells/kg was 39.5 x 10(6) (range: 5.2-221.2 x 10(6)). Subset analysis demonstrated the number of CD38(-), CD33(-), and CD133(+) peaked at day 11; and CD34(+), CD90(+) cells peaked at day 10. The optimum day for leukapheresis was determined to be day 11. The median absolute peripheral blood CD34(+) cell numbers on day 11 was 665 x 10(6)/l (range: 76-1481 x 10(6)/l). Eight of the 10 heavily pretreated patients were evaluable: three achieved the target dose in one leukapheresis (37.5%) and three (37.5%) achieved the target dose with two leukaphereses. Use of this mobilization strategy allowed the collection of high numbers of CD34(+) cells and early progenitors and the ability to predictably schedule leukapheresis.
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PMID:Optimising parameters for peripheral blood leukapheresis after r-metHuG-CSF (filgrastim) and r-metHuSCF (ancestim) in patients with multiple myeloma: a temporal analysis of CD34(+) absolute counts and subsets. 1247 76

E3 ubiquitin ligases are a large family of proteins that can be classified into three major structurally distinct types: N-end rule E3s, E3s containing the HECT (Homology to E6AP C-Terminus) domain, and E3s with the RING (Really Interesting New Gene) finger, including its derivatives, the U- Box and the PHD (Plant Homeo-Domain). E3 ubiquitin ligases exist as single polypeptide or multimeric complexes. Together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2, E3 ubiquitin ligases catalyze the ubiquitination of a variety of protein substrates for targeted degradation via the 26S proteasome. E3 ubiqutin ligases, therefore, play an essential role in regulation of many biological processes. Furthermore, E3s are enzymes that determine the specificity of protein substrates; they represent a class of "drugable" targets for pharmaceutical intervention. In this review, I will mainly focus on E3 ubiquitin ligases as potential cancer targets and discuss three of the most promising E3s, Mdm2/Hdm2, IAPs, and SCF, for their target rationales, target validation, and critical issues associated with them. These E3 ligases or their components are overexpressed in many human cancers and their inhibition leads to growth suppression or apoptosis. In addition, I will evaluate two current methodologies available for the high throughput screening for small molecular weight chemical inhibitors of the E3 ubiquitin ligases. Although targeting E3 ubiquitin ligases is still in its infancy, speedy approval of the general proteasome inhibitor, Velcade (bortezomib) by the FDA for the treatment of relapsed and refractory multiple myeloma suggests the promise of specific E3 inhibitors in anti-cancer therapy. Emerging technologies, such as siRNA, will provide a better validation of many E3s. It is anticipated that E3 ubiquitin ligases will represent an important new target platform for future mechanism-driven drug discovery.
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PMID:Targeting E3 ubiquitin ligases for cancer therapy. 1468 65

IL-6 has been reported to play a central role in growth and survival of multiple myeloma (MM) cells. However, recently we have demonstrated that in the presence of bone marrow stromal cells, survival of MM cells becomes independent of the IL-6/gp130/STAT3 pathway questioning the singular role of IL-6 in MM. Therefore, it was the aim of this study to identify additional factors and signaling pathways that might contribute to the growth and survival of MM cells. We found that in addition to IL-6 a number of bone marrow derived cytokines such as LIF, VEGF, bFGF, MIP-1alpha, SDF-1alpha, IL-1beta, SCF and IL-3 activate the MAPK pathway and induce proliferation of MM.1S and RPMI-8226 MM cells. In addition, these cytokines independently phosphorylate the forkhead family member FKHR via PI3-K/AKT and support survival of primary human MM cells. Inhibition of these pathways induces apoptosis in MM cell lines and primary MM cells. Thus, we provide evidence that in addition to IL-6 a number of different factors trigger important growth-promoting pathways to support the proliferation and survival of MM cells. Therefore, blocking such pathways, rather than blocking a single factor, might be a promising approach for the development of novel treatment strategies in MM.
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PMID:PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. 1535 48

The molecular basis for aggressive transformation of multiple myeloma (MM) and other cancers is not completely understood. Global gene expression profiling on highly purified malignant plasma cells from 351 newly diagnosed patients with MM treated with autologous stem cell transplantation revealed a statistically significant over-representation of chromosome 1 genes in a group of 70 genes whose expression was linked to poor outcome. In particular, over-expression of CKS1B, which maps to an amplicon at 1q21 in myeloma and regulates SCF(Skp2)-mediated ubquitination and proteolysis of the cyclin dependent kinase inhibitor p27Kip1 was significantly over-expressed in patients with poor survival. Interphase fluorescence in-situ hybridization revealed that CKS1B expression was strongly correlated with DNA copy number in a subset of 197 cases (P<0.0001) with both measurements. Validated in 224 patients lacking expression analysis, CKS1B gene amplification conferred a poor prognosis (P<0.0001) and was an independent predictor of outcome in multivariate analyses (P=0.002). CKS1B mRNA and protein expression were correlated and both were inversely correlated with p27(Kip1) protein levels. RNA interference of CKS1B messenger RNA in myeloma cell lines led to reduced CKS1B mRNA and protein, an accumulation of p27Kip1, and profound growth inhibition. Based on these data we conclude that over-expression of CKS1B, mainly due to gene amplification, imparts a poor prognosis in MM, possibly as a result of enhanced degradation of p27Kip1.
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PMID:Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. 1618 52

To explore the effects of proteasome inhibitor PS-341 on the cytokine expressions of mesenchymal stem cells (MSC) in patients with multiple myeloma (MM), MSCs of 11 patients were cultured in medium of RPMI 1640 containing 10% FBS. When cells grew to 5 x 10(5) - 1 x 10(6), cells were exposed to 50 nmol/L PS-341 for 4 hours, then harvested. The expressions of IL-6, IL-1beta and SCF were detected by RT-PCR. The results indicated that after treatment with PS-341 the expressions of IL-6, IL-1beta and SCF of MSCs decreased markedly, especially that of IL-1beta, compared with control (P < 0.05, P < 0.01, P < 0.05, respectively). There were obviously differences of IL-1beta expression between refractory/relapsed group and complete remission (CR) group and IL-1beta expression was inhibited more seriously in CR group, whereas there were no significant differences of IL-6 and SCF expression between two groups; IL-1beta expression of patients treated with PS-341 was not detected; there were not effects of IL-1beta expression on expressions of IL-6 and SCF. It is concluded that proteasome inhibitor PS-341 downregulated the expressions of IL-6, IL-1beta and SCF of MSCs in patients with MM.
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PMID:[Effects of proteasome inhibitor PS-341 on the multiple cytokine expressions of mesenchymal stem cells from bone marrow in patients with multiple myeloma]. 1658 93

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