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)

Biological heterogeneity is a characteristic of multiple myeloma. A dysregulated cytokine network underlies the various phases of the disease. Numerous cytokines, either promoting or inhibiting plasma cell growth, are involved in tumor control. Interferon-gamma (IFN-gamma) showed the most powerful inhibiting activity on myeloma cell proliferation. This effect was demonstrated on IL-6 dependent myeloma cell lines, but not on IL-6 independent ones. It was also evident on fresh explanted bone marrow myeloma cells. The antiproliferative effect of IFN-gamma seems mainly due to the inhibition of IL-6, the central myeloma growth factor. IL-6 inhibition may occur at various levels: a downregulation of IL-6 receptor has been reported, and also a block of the IL-6 signal transduction pathway via interaction with cytoplasmic proteins such as p91 has been suggested. Our findings showed that IFN-gamma strongly inhibited myeloma cell proliferation to the same extent as dexamethasone (DEX), whereas interferon-alpha (IFN-alpha) inhibited Ig secretion. The combined use of interferons (IFNs) showed inhibitory activities both on proliferation and Ig synthesis that paralleled the effects of DEX. In some cases, IFN-gamma was also shown to augment monoclonal immunoglobulin secretion suggesting a possible differentiating activity on plasma cells. The in vitro data encouraged pilot studies to evaluate the in vivo antitumor effects of IFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-gamma in multiple myeloma. 853 85

Haemopoietic recovery is more rapid after peripheral blood stem cell (PBSC) transplantation than after autologous bone marrow transplantation, and the aim of this study was to assess the role of the large number of lymphocytes and monocytes (accessory cells) in a PBSC leukapheresis product in this rapid regeneration. Haematological recovery was therefore assessed in 10 PBSC recipients with lymphoma or myeloma in whom monocytes and T cells were depleted by a median of 2.3 and 3.3 logs by CD34+ cell selection using the CEPRATE SC stem cell concentration system and compared with recovery in 59 recipients who received whole PBSC. After allowing for the number of progenitor cells reinfused, there was no significant delay in engraftment induced by accessory cell depletion. Plasma levels of granulocyte-colony stimulating factor (G-CSF), granulocyte/monocyte-colony stimulating factor (GM-CSF), interleukin-6 (IL-6), stem cell factor (SCF) and macrophage-inhibition factor-alpha (MIP-1-alpha) during the transplant procedure were similar whether or not accessory cells were given. The G-CSF and IL-6 levels rose between days 5 and 14 post transplantation to approximately 1 ng/ml and 50 pg/ml respectively. This study indicates that accessory cells reinfused with PBSC collections are not responsible for the subsequent cytokine profile or rapid haematological recovery.
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PMID:Accessory cells do not contribute to G-CSF or IL-6 production nor to rapid haematological recovery following peripheral blood stem cell transplantation. 855 91

Paget's disease of bone and multiple myeloma are characterized by increased numbers of osteoclasts and markedly increased bone resorption at the sites of the disease. In Paget's disease the osteoclasts are abnormal morphologically and contain viral-like nuclear inclusions, but in multiple myeloma the osteoclasts are normal. The bone lesions in both Paget's disease and multiple myeloma appear to be due to local stimulation of osteoclast formation and bone resorption. In situ hybridization techniques, bone marrow cultures, and cytokine assays have been used to examine osteoclast function in Paget's disease and multiple myeloma. Interleukin-6 (IL-6) has been implicated as a potential mediator for the increased osteoclast activity in both diseases. In Paget's disease, IL-6 is produced by the osteoclasts, the osteoclasts express IL-6 receptors and IL-6 mRNA, and increased levels of IL-6 are present in the marrow plasma and serum of these patients. Similarly, increased levels of IL-6 have been detected in sera from some patients with multiple myeloma. Multiple myeloma cells do not produce IL-6 in vivo but marrow stromal cells or the osteoclasts may be the source of IL-6 in multiple myeloma. IL-6 is a growth factor for multiple myeloma cells, and treating patients with anti-IL-6 decreases the tumor burden in some patients. Thus, IL-6 may be an autocrine/paracrine factor in both Paget's disease and in multiple myeloma. Multiple myeloma cells also produce osteoclast activating factors (OAFs) that can stimulate osteoclast formation and activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Osteoclast function in Paget's disease and multiple myeloma. 857 99

The polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder of obscure pathogenesis associated with osteosclerotic myeloma. Circulating levels of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) interleukin-1 beta [IL-1 beta], IL-2, IL-6, and interferon-gamma [IFN-gamma]), anti-inflammatory cytokines (transforming growth factor beta 1 [TGF beta 1], IL-4, IL-10, and IL-13), the cytokine carrier protein alpha 2 macroglobulin, IL-1 receptor antagonist (IL-1ra), soluble TNF receptors (sTNFr) p55 and p75, and soluble IL-6 receptor (sIL-6r) were determined in 15 patients with POEMS syndrome and 15 with multiple myeloma. Patients with POEMS syndrome had higher serum levels of IL-1 beta, TNF-alpha, and IL-6 and lower serum levels of TGF beta 1 than did patients with multiple myeloma. Serum levels of IL-2, IL-4, IL-10, IL-13, IFN-gamma, alpha 2 macroglobulin, and sIL-6r were similar in both groups. IL-1ra and sTNFrs were increased in POEMS syndrome, but out of proportion to the increase of IL-1 beta and TNF-alpha. Serial evaluations in 1 patient showed that proinflammatory cytokine serum levels paralleled disease activity assessed by platelet count and neurologic involvement. Our results suggest that the manifestations of POEMS syndrome might be regarded as the result of a marked activation of the proinflammatory cytokine network (IL-1 beta, IL-6, and TNF-alpha) associated with a weak or even decreased (TGF beta 1) antagonistic reaction insufficient to counteract the noxious effects of cytokines.
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PMID:Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. 860 36

Multiple myeloma (MM) remains incurable. Despite many chemotherapy programs for large numbers of patients, there has been little improvement in outcome during the past 25 years. For many years, intermittent courses of melphalan and prednisone have represented the standard chemotherapy for newly diagnosed symptomatic MM. Many other drug combinations have been assessed, including regimens using multiple alkylating agents, and programs with vincristine, or an anthracycline, and have failed to show any superiority to melphalan-prednisone. Interferon alpha (IFN alpha) inhibits plasma cell growth and has induced responses in approximately 15% of previously untreated patients. This cytokine may have a role when used in those patients who have reached a good "plateau phase" with low tumor burden at the end of a chemotherapeutic program or after a transplantation procedure. The results of myeloablative therapy with allogenic or autologous marrow transplantation are promising and suggest possibility of a cure in some patients. Important problem in the management of MM patients is the treatment of complications, especially bone destruction, hypercalcemia, anemia and infections. Experimental modalities, especially immunotherapy, hold promise for use in humans and may also provide further insights into the pathogenesis of MM.
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PMID:[Treatment of multiple myeloma--present status and perspectives]. 862 44

An inhibitor of IL-6 binding to the human hepatoma line HepG2 and myeloma cell line U266 was identified in a saline extract of the marine sponge, Callyspongia sp. Functional activity, measured through the increase in haptoglobin production by HepG2 cells stimulated with IL-6, could be strongly inhibited by the extract. Similarly, IL-6-induced production of IgM by the B cell line SKW6.4 was substantially reduced. In neither cell line was there evidence of toxicity produced by the extract. Other sponges of the Callyspongia species were found to contain analogous activity. The activity was destroyed by trypsin treatment or boiling of the extract, suggesting that the inhibition is due to a protein. When the binding of IL-6 to its receptor complex was dissected in vitro, inhibition of binding of IL-6 to soluble receptor by the extract was not detected, but binding of the IL-6-sIL-6R complex to soluble gp130 was inhibited in a dose-dependent fashion. This was borne out in cellular assays since the extract inhibited activation of HepG2 cells stimulated with oncostatin M or leukemia inhibitory factor, cytokines which also use gp130 for signal transduction. These results suggest that the Callyspongia extract contains a protein which blocks the interaction of the IL-6 family of cytokines with their signal transduction moiety, gp130. Elucidation of the structure and mode of action of such a protein would be helpful in designing gp130 antagonists to inhibit the functions of this cytokine family, overproduction of which has been associated with cancer and pathologies of autoimmune disease and AIDS.
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PMID:Characterization of an interleukin 6 cytokine family antagonist protein from a marine sponge, Callyspongia sp. 863 42

Interleukin-6 (IL-6) is the major growth factor for myeloma cells and is believed to participate in the pathogenesis of chronic autoimmune diseases and postmenopausal osteoporosis. IL-6 has been recently shown to possess three topologically distinct receptor binding sites: site 1 for binding to the subunit specific chain IL-6R alpha and sites 2 and 3 for the interaction with two subunits of the signaling chain gp130. We have generated a set of IL-6 variants that behave as potent cytokine receptor super-antagonists carrying substitutions that abolish interaction with gp130 at either site 2 alone (site 2 antagonist) or at both sites 2 and 3 (site 2 + 3 antagonist). In addition, substitutions have been introduced in site 1 that lead to variable increases in binding for IL-6R alpha up to 70-fold. IL-6 super-antagonists inhibit wild-type cytokine activity with efficacy proportional to the increase in receptor binding on a variety of human call lines of different origin, and the most potent molecules display full antagonism at low molar excess to wild-type IL-6. When tested on a representative set of IL-6-dependent human myeloma cell lines, although site 2 super-antagonists were in general quite effective, only the site 2 + 3 antagonist Sant7 showed antagonism on the full spectrum of cells tested. In conclusion, IL-6 super-antagonists are a useful tool for the study of myeloma in vitro and might constitute, in particular Sant7, effective IL-6 blocking agents in vivo.
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PMID:Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells. 863 18

The chemotaxis of human malignant plasma cells is promoted by two extracellular matrix proteins (ECMs): fibronectin (FN) and laminin (LN). We examined the effect of the supernatant from a bone marrow stroma cell line, KM-101, on the chemotaxis of human malignant plasma cell lines to assess the chemotaxis-regulatory roles of the bone marrow microenvironment. Five human malignant plasma cell lines, FR4ds, OPM-1ds, U266/B1, RPMI-8226 and ARH-77 showed different profiles of the expression of beta 1 integrins of FN and LN receptors. FR4ds, OPM-1ds and U266/B1 cells showed chemotaxis promoted by FN (ChFN) and LN (ChLN). ARH-77 cells showed ChFN but not ChLN. RPMI-8226 cells did not show either ChFN or ChLN. The supernatant from KM-101 cells inhibited the chemotaxis of each of these cell lines regardless of whether the chemotaxis was promoted by FN or LN. Among the cytokines produced by KM-101 cells, it was postulated that IL-6 mediated this inhibitory effect because anti-IL-6 monoclonal antibody (MoAb) and anti-IL-6 receptor MoAb significantly reversed the inhibition. Recombinant IL-6 (rIL-6) also exhibited a similar inhibitory effect. Because anti-gp130 MoAb significantly reversed the chemotaxis inhibitory effect of rIL-6, the inhibitory signal is probably transduced via the signal transducing receptor component, gp130. The chemotaxis-regulatory effect is another previously unrecognized function of this pleiotropic cytokine, IL-6. High levels of IL-6 in the bone marrow microenvironment of patients with multiple myeloma appears to be favourable for the localization of myeloma cells there.
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PMID:Interleukin-6 inhibits the chemotaxis of human malignant plasma cell lines. 865 70

The cytokine IL-6 has been proposed as an autocrine growth factor in multiple myeloma, and is also required for stimulation of immunoglobulin production and secretion in normal plasma cells and myeloma cells. In this study, we showed that secreted IL-6 is detectable by Western blot analysis in a panel of lymphoid and myeloma cell lines. Previous studies in our laboratory have shown that dexamethasone and suramin inhibit cell proliferation and IL-6-mediated immunoglobulin secretion in various lymphoblastoid and myeloma cell lines. In the present study, we present study, we present data to examine mechanisms by which dexamethasone and suramin inhibit IL-6-mediated immunoglobulin secretion in the lymphoid cell line SKW 6.4. Cells treated with rIL-6 or the IC10 concentration of dexamethasone respectively undergo a doubling of intracellular IgM. Moreover, rIL-6 and dexamethasone additively stimulate cells to accumulate intracellular IgM. In contrast, cells treated with the IC10 concentration of suramin undergo no significant alteration of total cellular IgM, and do not respond to IL-6 with an increase in intracellular IgM. Northern blot analysis demonstrates that cells treated with exogenous rIL-6 and/or dexamethasone respectively undergo a coordinate one to three fold increase of kappa and mu chain mRNA expression, while there is a 30-40% decrease of kappa and mu chain mRNA when cells are treated with suramin and suramin plus rIL-6. Western blot analysis shows that levels of intracellular IL-6 modestly increase when cells are treated with exogenous rIL-6, whereas treatment with dexamethasone plus rIL-6 causes a 70% decrease of immunoreactive IL-6 protein in comparison with untreated cells. An rtPCR analysis of IL-6 mRNA expression shows an abolished signal in response to dexamethasone or rIL-6 and/or dexamethasone. Using a flow cytometric assay, it is demonstrated that suramin inhibits IL-6 binding to its receptor. Taken together, these results indicate that SKW 6.4 cells treated with rIL-6 and/or dexamethasone undergo increased expression of IgM mRNA leading to increased intracellular IgM levels. Treatment with suramin or suramin plus rIL-6 does not alter the IL-6 protein level or the mRNA levels for IL-6 and IL-6 receptor. Suramin treatment causes a moderate decrease in IgM mRNA, and this is associated with a decreased intracellular level of IgM in SKW 6.4 cells. Overall these findings support the concept that IL-6 is an autocrine factor for immunoglobulin production and secretion in myeloma cells. Suramin interferes with IL-6 binding to its receptor and/or decreases IL-6 receptor expression. Dexamethasone has neither of these effects on IL-6 receptor expression or IL-6 binding to its receptor, and we postulate that it acts through a block in secretion or in degradation of intracellular immunoglobulin by decreasing IL-6 mRNA expression and IL-6 protein content. These studies suggest that the combination of suramin and dexamethasone not only synergistically growth inhibit myeloma cells but also act in concert to inhibit immunoglobulin secretion and represent a therapeutic approach worthy of further investigation.
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PMID:Mechanisms of inhibition of IL-6-mediated immunoglobulin secretion by dexamethasone and suramin in human lymphoid and myeloma cell lines. 872 10

High-dose cyclophosphamide (HD-CY) has been shown to decrease the tumor mass in multiple myeloma (MM) patients and to be effective in the mobilization of PBPC. By administering hematopoietic growth factor the quantity of progenitor cells in the peripheral blood increased and the hematological toxicity of CY could be reduced. Thirty-two patients with stage II and stage III MM were treated to mobilize and harvest a sufficient amount of PBPC for autologous transplantation. Sixteen patients received 4 g/m2 CY and 16 patients 7 g/m2 CY in divided doses of 1 g/m2 every 2 h. Both patient groups were comparable for disease stages as well as previous therapies. Twenty-four hours after chemotherapy 300 micrograms GCSF were administered subcutaneously once daily until the last day of leukapheresis. Administration of 7 g/m2 HD-CY resulted in statistically significantly higher peak values for CD34+ progenitor cells (47.86/microliters vs 18.75/microliters, P = 0.0198) in the peripheral blood. PBPC autografts containing > 2.5 x 10(6) CD34+ cells/kg BW could be obtained at the first attempt from 14 of 16 patients treated with 7 g/m2 CY as compared to 10 of 16 patients treated with 4 g/m2 CY (P = 0.11). The analysis of potentially malignant CD19+ B cells showed a highly significant lower mean CD19+ cell content/kg BW per leukapheresis in the 7 g/m2 compared to the 4 g/m2 CY group (0.75 vs 1.81 x 10(6), P = 0.001). WHO grade IV treatment-related non-hematologic toxicity was not observed. We prefer the 7 g/m2 CY dosage followed by cytokine administration for the mobilization of PBPC in advanced state MM patients pretreated with alkylating agents.
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PMID:Mobilization of peripheral blood progenitor cells with high-dose cyclophosphamide (4 or 7 g/m2) and granulocyte colony-stimulating factor in patients with multiple myeloma. 873 83

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