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)

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT-specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti-IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.
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PMID:Production of interleukin-1 by bone marrow myeloma cells. 266 38

Hypercalcemia of malignancy is caused by different mechanisms in different types of tumors. In most solid tumors, increased bone resorption and decreased urine calcium excretion are responsible. However, in myeloma, increased bone resorption and decreased glomerular filtration are the cause. In most solid tumors, factors working in conjunction cause the hypercalcemic syndrome. In addition to PTHrP, these include transforming growth factor alpha, interleukin-1, tumor necrosis factor, and lymphotoxin.
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PMID:Hypercalcemic factors other than parathyroid hormone-related protein. 267 74

Abnormal bone remodelling in the vicinity of tumor cells is a common, early feature of multiple myeloma, characterized by excessive bone resorption which is mediated by local soluble factors called osteoclast activating factors (OAF). Since interleukin-1 (IL-1) and tumor necrosis factors (TNF) are potent, synergistic OAF produced by cells of the B-cell lineage, the authors investigated the spontaneous secretion of these cytokines by 11 human myeloma cell lines (HMCL). No HMCL secreted either IL-1, the most powerful OAF, or contra IL-1. In contrast, all of the lymphoblastoid cell lines assayed produced significant IL-1 activity. Ten of the 11 HMCL secreted a significant TNF activity. This was completely eliminated by an anti-TNF beta monoclonal antibody but not affected by an anti-TNF alpha antiserum. The data from this study suggest that TNF beta is involved in myeloma bone resorption, but not IL-1, which is, however, known as one of the most potent OAF.
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PMID:Spontaneous secretion of tumor necrosis factor-beta by human myeloma cell lines. 278 61

Supernatants of freshly isolated human myeloma cell cultures were examined both for bone-resorbing activity (BRA) in vitro using newborn mouse calvaria, and for identification of the causal substances of the BRA. Eight of 14 culture supernatants of myeloma cells had BRA. All of these BRA-positive supernatants were from patients with marked destructive bone lesions of multiple myeloma. The presence of interleukin 1 (IL-1), especially IL-1 beta, was demonstrated in seven of these BRA-positive supernatants but not in BRA-negative supernatants. The concentrations of IL-1 beta were high enough to induce bone resorption in the newborn mouse calvaria assay and the BRA was totally abolished by pretreatment of the supernatants with anti-IL-1 beta antibody but not with either anti-IL-1 alpha antibody or normal serum. Other bone resorbing cytokines such as tumor necrosis factor or lymphotoxin were not present in high enough concentrations to stimulate bone resorption and their levels did not correlate with the BRA. IL-1 beta mRNA was also identified in BRA-positive myeloma cells. These results demonstrate that IL-1 beta is the principal agent of BRA present in supernatants of myeloma cell cultures, and also identify a possible role of IL-1 beta in destructive bone lesions in patients with multiple myeloma.
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PMID:Production of interleukin 1 beta, a potent bone resorbing cytokine, by cultured human myeloma cells. 278 4

Myeloma cells destroy bone by producing an osteoclast-stimulating factor that has chemical and biological characteristics similar to the bone-resorbing activity present in the supernatants of activated leukocyte cultures. Recently, a number of bone-resorbing leukocyte cytokines have been identified, including interleukin-1, lymphotoxin, and tumor necrosis factor. We have examined the products of human myeloma cells for the presence of these bone-resorbing cytokines. In a tumor cell line derived from a patient who had myeloma with osteolytic bone lesions and hypercalcemia, we found that the myeloma cells induced bone-resorbing activity and cytotoxic activity in vitro. Most of the bone-resorbing activity and all cytotoxic activity were suppressed by neutralizing antibodies to lymphotoxin. The myeloma cells expressed both lymphotoxin and tumor necrosis factor mRNA, but no tumor necrosis factor could be detected in the cell-culture medium. Interleukin-1 mRNA was not detected in the myeloma cells, and biologic activity of interleukin-1 was not measurable in the medium harvested from the cultured cells. The bone-resorbing activity induced by recombinant tumor necrosis factor and recombinant interleukin-1 was not affected by treatment with the lymphotoxin antibodies. When lymphotoxin was infused subcutaneously into normal mice (10 micrograms per day for three days), their plasma calcium levels increased. We also evaluated four established cell lines derived from three other patients with myeloma, and found a similar pattern of lymphotoxin expression in each. It appears that production of the bone-resorbing cytokine lymphotoxin is related to osteoclastic bone destruction and hypercalcemia in patients with myeloma.
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PMID:Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells. 349 47

Plasma cell malignancy, multiple myeloma, is the prototype of monoclonal terminal-differentiated B cell proliferation that reveals a monoclonal Ig in the serum and/or urine of the majority of patients. New insights into the biology and pathogenesis of this entity are based on careful research to a complex cytokine network including TNF beta, IL-1 beta, and IL-6, many oncogene products such as bc1-2 protein, H-ras p-21 protein, and RB-1 product, and cell surface antigens associated with myeloma cells. The recent understanding on the mechanism for acquisition of IgV region diversity during B cell development has clarified the origin of the clonogenic cell in multiple myeloma. Further identification of new prognostic parameters as well as new therapeutic agents is necessary for the rational therapy of this refractory malignancy.
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PMID:[Advances in biology and pathogenesis of multiple myeloma]. 769 96

The etiology and pathophysiology of bone lesions in multiple myeloma (MM) and the new treatment for bone lesions in MM are mentioned in this report. The osteoclastic activating factors (OAF) include lymphotoxin (TNF-beta), interleukin 1, tumor necrosis factor (TNF-alpha) and several other cytokines. MM patients with multiple bone lesions have low bone density and low serum 1,25-hydroxyvitamin D level. The measurement of bone mineral density using dual-energy X-ray absorptiometry is useful to evaluate the bone lesions in MM. New diphosphates, which strongly inhibit the activity of osteoclasts, are now expected to be effective in the treatment of bone lesions in MM.
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PMID:[Bone lesions in multiple myeloma]. 769 4

Human myeloma cells have been supposed to produce osteoclast activating factors (OAF) that stimulate osteoclasts. The OAF from myeloma cell lines and freshly isolated myeloma cells has been attributed to TNF beta and IL-1 beta, respectively, although production of these cytokines is still controversial. Because of the bone resorption and latent renal dysfunction, hypercalcemia appears to develop readily in myeloma patients. The level of the cytokine production by myeloma cells appears to be relatively low; however, it may be sufficient to activate osteoclasts, because myeloma cells are present close to them. Recently, PTH-rP has been suggested to be involved in the bone resorption. In addition to conventional treatment of hypercalcemia, bisphosphonate may be a usefull tool to inhibit bone resorption.
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PMID:[Hypercalcemia in multiple myeloma]. 769 10

The authors review contemporary findings on the role of different components of the cytokine network from the aspect of development, prognosis and treatment of multiple myeloma. Greatest attention was devoted to the main growth factor of myeloma elements IL-6, but also to the real or so far sparsely elucidated role of other cytokines (IL-1, IL-2, GM-CSF, G-CSF, IL-3, IL-4, IL-5, IL-10, TNF, interferon alpha and gamma) under conditions in vitro and in vivo. For completeness sake the authors did not omit the problem of the soluble receptor of IL-2 and the role of TNF, TNF beta and in particular IL-1 beta in the pathogenesis of osteolytic lesions and the potential therapeutic role of antibodies against IL-6 (anti IL-6 mab) and interferon alpha and gamma.
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PMID:[The cytokine network in multiple myeloma]. 794 39

T cells in multiple myeloma (MM) patients are highly susceptible to activation with the anti-CD3 monoclonal antibody (mAb) OKT3. When short-term OKT3 stimulation is carried out on bone marrow mononuclear cells (BMMC), large numbers of CD3+ CD25+ HLA-DR+ cells are rapidly generated and autologous malignant plasma cells are killed. OKT3 may thus be exploited in autologous bone marrow transplantation (ABMT) to purge residual plasma cells and simultaneously activate T cells to induce graft-versus-leukemia-like (GVL-like) activity upon reinfusion. However, the possible impact of ex-vivo short-term OKT3 stimulation on haematological recovery is unknown. The aim of this work was to investigate the effect of OKT3 stimulation in vitro on autologous haemopoietic progenitor cells (HPC) of MM patients. Colony formation by granulocyte-macrophage progenitor cells (granulocyte-macrophage colony-forming units, CFU-GM) was highly suppressed, although supernatants of OKT3-activated T cells contained up to 2,500 pg/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF). T cell depletion completely prevented this suppression. Neutralizing antibodies against TNF-alpha, TNF-beta and IFN-gamma (which are also produced by OKT3-activated MM T cells) did not prevent it, and Transwell cultures showed that cell-to-cell contact was the main mechanism involved. OKT3-activated T cells also suppressed erythroid burst-forming units (BFU-E) and CFU-GM generation from HPC responsible for long-term maintenance of in vitro myelopoiesis. When tested on normal allogeneic BM, MM supernatants of OKT3-stimulated BMMC partially suppressed the generation of day 7 CFU-GM, but had no effect on day 14 CFU-GM. These data indicate that short-term stimulation of BMMC with OKT3 can be used to generate anti-tumour effector T cells for autologous adoptive immunotherapy. It is not a feasable approach for ex-vivo purging and activation procedures in ABMT because of its potent inhibition of autologous haemopoiesis.
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PMID:Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma: in vitro inhibition of autologous haemopoiesis. 799 89


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