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)

Tumor necrosis factor (TNF-alpha) acts as a growth stimulatory factor on leukemic B lymphocytes from many patients with chronic lymphocytic leukemia (CLL). Because TNF induces production of interleukin-6 (IL-6), which has been shown to be a growth factor for myeloma and other transformed B cells, we examined the possibility that IL-6 mediates the growth-stimulatory effect of TNF on B-CLL cells. In fact, we found that IL-6 is an inhibitor of B-CLL growth. The addition of recombinant human IL-6 markedly decreased the TNF-induced B-CLL growth, and this decrease was even greater when soluble IL-6 receptor, known to act as IL-6 agonist, was added with recombinant IL-6. Conversely, neutralizing monoclonal antibodies to IL-6 and to the IL-6 receptor potentiated the growth stimulation of TNF on B-CLL cells, in line with the possibility that IL-6 functions as a negative feedback regulator of an autocrine TNF action on these B-leukemic cells. Evidence is presented that production of IL-6 by monocytes and B cells of CLL patients is low, suggesting that administration of IL-6 may be beneficial in CLL to reduce the eventual growth stimulation by TNF and, possibly, also the deficiency in platelets and Ig production in this disease.
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PMID:Interleukin-6 inhibits the proliferation of B-chronic lymphocytic leukemia cells that is induced by tumor necrosis factor-alpha or -beta. 838 26

In this review, the pathophysiology and treatment of the anemia of multiple myeloma will be examined. While the anemia of cancer has multiple causes, an important component is labeled the "anemia of chronic disease" which is characterized by the combination of a shortened erythrocyte survival with failure of the bone marrow to increase red cell production in compensation. Depressed erythropoiesis is itself related to a combination of factors, including impaired availability of storage iron, inadequate erythropoietin response to anemia, and overproduction of cytokines which are capable of inhibiting erythropoiesis. These cytokines are involved in the retention of iron in the reticuloendothelial system, gastrointestinal tract and hepatocytes, may interfere with erythropoietin production by the kidney, and may exert direct inhibitory effects on erythroid precursors. While overproduction of several such cytokines, including IL-6, IL-1 and TNF-alpha, has been definitely demonstrated in multiple myeloma patients, it is still unclear whether they are directly involved in the pathogenesis of the anemia which develops. Although several mechanisms, such as hemodilution, bleeding, and decreased red cell survival operate, the anemia is mostly caused by defective erythropoietic activity. This in turn is partly explained by inadequate erythropoietin (Epo) production even in some patients without renal impairment. Based on measurements of serum erythropoietin and transferrin receptor, the distinction between marrow unresponsiveness to normal Epo stimulation and deficient Epo production is important for the treatment of the anemia of multiple myeloma with recombinant human Epo. Higher doses would probably be necessary if adequate Epo production is present, whereas only replacement therapy with lower doses may be sufficient when Epo production has been shown to be inappropriate.
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PMID:Erythropoiesis and erythropoietin in multiple myeloma. 852 47

The authors have recently shown that antibodies with anti-idiotype (Id) specificity to pathogenic Ids of lupus nephritis may occasionally occur in several intravenous immune globulin (IVIG) preparations because they are present in healthy donors and the healthy relatives of SLE patients. In the present study, the authors purified these anti-Ids and treated two SLE patients with nephritis in parallel with conventional high-dose IVIG management with a commercial preparation (IVIG 6) in three controls for two months. Because pathogenic Ids of anti-DNA molecules, such as both 8.12 and F4 Ids, show a cationic mobility in isoelectric focusing, a commercial preparation of IVIG (11) was absorbed on a Sepharose column coupled with DC-305-39 myeloma protein, namely an 8.12+ and F4+ cationic IgG. Infusion of the eluate (EL-11) induced a prompt resolution of proteinuria levels and an evident decrease of serum levels of anti-DNA antibodies in both patients, whereas in the three controls, proteinuria and anti-DNA antibodies were scarcely reduced. In addition, plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were also significantly influenced by both treatments. The mean values of both cytokines increased significantly after 1 h and then progressively declined over the next 48 h. It was of interest, however, that the increased TNF-alpha in the two EL-11-treated patients was significantly lower than in the three controls. The data suggest that reduction of active lupus nephritis by enriched specific anti-Id molecules is the result of two (or perhaps more) mechanisms: suppression of pathogenic idiotypes at the cellular level and improvement in the mesangium of the secretion of anti-inflammatory cytokines, such as IL-6, whose defective function is related to the autoimmune disorder.
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PMID:Intravenous immune globulin therapy of lupus nephritis: use of pathogenic anti-DNA-reactive IgG. 862 51

Multidrug resistance (MDR) is a phenomenon by which tumor cells exposed to a single anti-proliferative agent acquire resistance to other structurally and functionally unrelated drugs. The classical form of MDR is caused by a plasma-membrane protein currently named P-glycoprotein or P-170 encoded by the human mdr-1 gene in its functional isoform. In vitro cell lines expressing P-170 usually also present phenotypic and functional alterations. In the present study we report that the cytotoxicity mediated by tumor necrosis factor alpha (TNF alpha) in MDR variants of the human T-lymphoblastoid CEM cell line is associated with apoptosis (programmed cell death). Susceptibility of MDR cells to apoptosis was increased upon cycloheximide + TNF alpha sequential treatment, whereby the impairment of protein synthesis due to the former agent was followed by the effect of cytokine exposure. Massive apoptosis of P-170-positive cells, but not of controls, was also obtained by depletion of nutrients (i.e., serum starvation). In contrast, TNF-alpha exerted a similar apoptotic effect in epithelial (MCF-7) or myeloma (S8226) drug-sensitive/ -resistant cell pairs. However, the MDR variant of myeloma S8226 was more sensitive to the cytostatic effect of TNF alpha than the parental drug-sensitive cell line. These results suggest that the presence of the MDR phenotype may be associated with increased histotype-dependent cell susceptibility to specific, protein-synthesis-independent, apoptotic pathways.
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PMID:Tumor necrosis factor alpha is a powerful apoptotic inducer in lymphoid leukemic cells expressing the P-170 glycoprotein. 876 May 94

The Polyneuropathy, Organomegaly, Endocrinopathy, M protein, Skin changes (POMEMS) syndrome is a rare multisystem disorder of obscure pathogenesis, associated with osteosclerotic myeloma. Unlike multiple myeloma without neuropathy, circulating levels of proinflammatory cytokines (IL-1 beta, TNF-alpha IL-6) are increased in patients with POEMS syndrome. Sites of IL-1 beta production include lymph node and bone marrow tissues. These data support the view that pleiotropic effects of proinflammatory cytokines released secondary to a strong activation of the monocyte/macrophage system, take part in the multisystemic expression of the disease.
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PMID:[Pro-inflammatory cytokines: a pathogenic key of POEMS syndrome]. 888 41

Cytokine messenger RNA expression was studied using the reverse transcription/polymerase chain reaction in 23 patients with multiple myeloma (MM), 16 with monoclonal gammopathy of undetermined significance (MGUS), 12 with post menopausal osteoporosis, (OP) and 12 normal controls. Messenger RNAs for IL-1 alpha, IL-1 beta, TNF-alpha, TNF-beta, IL-6 and M-CSF were sought in view of their reported pathogenic role in myeloma. Transcripts for IL-1 beta, TNF-alpha, TNF-beta and M-CSF were found frequently in all four groups of patients. The only significant difference in cytokine expression between the groups was for IL-6 which was expressed in 17% of controls compared with 87% of patients with MM (p < 0.001), 62% of patients with MGUS (p < 0.02) and 67% of patients with osteoporosis (p < 0.02). Further analysis of IL-6 expression by quantitative PCR showed significantly higher IL-6 mRNA levels in MM compared with MGUS (p < 0.006). There was no correlation however between expression of individual cytokines and clinical features of myeloma such as osteolytic bone disease or hypercalcaemia. We conclude that expression of IL-6 mRNA is significantly enhanced in multiple myeloma when compared with MGUS. However, since MGUS and osteoporosis were also associated with a high prevalence of IL-6 expression when compared with controls it is probable that factors other than IL-6 are responsible for the local osteolytic lesions which characterise MM, but which are not seen in MGUS or osteoporosis.
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PMID:Cytokine expression in multiple myeloma and monoclonal gammopathy: analysis by reverse transcription/polymerase chain reaction and quantitative PCR. 904 67

Crosslinking of immunoglobulin E molecules that are bound to the Fc epsilon receptors expressed on mast cells or basophils triggers activation of these cells, resulting in the development of a type I hypersensitivity. Targeting this potent immune reaction towards tumors by using IgE that reacts with a tumor-associated antigen, may induce a local inflammation at the tumor site, and may therefore promote tumor regression. We have previously shown that murine IgE bound to tumor cells can activate murine mast cells to release TNF-alpha and histamine. To further investigate the therapeutic potential of IgE-mediated immunotherapy of carcinomas, we have developed human/murine chimeric versions, containing the murine variable regions and human constant regions, of both G250 and 323/A3 IgE. These chimeric IgEs are reactive respectively with the G250 renal cell carcinoma antigen and the Ep-CAM molecule, which is highly expressed by most carcinomas. Transfection of the respective chimeric heavy and light chain genes into recipient Sp2/0 myeloma cells yielded chimeric IgE-producing clones. Chimeric G250 and 323/A3 IgE reacted with tumor cells expressing the G250 antigen or Ep-CAM, respectively. To generate a cell line that expresses Fc receptors for human or chimeric IgE, the rat basophilic leukemia cell line RBL-7 was transfected with the human Fc epsilon RI alpha chain (RBL-7TZ) and subsequently tested for binding of chimeric IgE. Functional assays showed that both chimeric IgEs activated RBL-7TZ cells to release TNF-alpha when cultured with tumor cells that express the respective specific antigen. Furthermore, both chimeric IgEs were able to activate freshly isolated human basophils.
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PMID:Chimeric immunoglobulin E reactive with tumor-associated antigen activates human Fc epsilon RI bearing cells. 939 19

In a previous study, culture of peripheral blood mononuclear cells (PBMC) from myeloma patients with interleukin(IL)-4 and tumour necrosis factor(TNF)-alpha resulted in the appearance of clonal plasma cells, thus suggesting the presence of circulating myeloma cell precursors in the peripheral blood. Using the same cytokine combination, we cultured PBMC and purified peripheral blood B-cells from myeloma patients. In nearly all cases, partial differentiation of B-cells occurred but, similarly to results for normal controls, both kappa and lambda light chain (L.C.) cytoplasmic positive lymphoid and lymphoplasmacytoid cells were detected rather than clonal plasma cells. These results suggest that IL-4 and TNF-alpha cause partial differentiation of residual normal polyclonal B-cells rather than of circulating myeloma cell precursors in the peripheral blood of myeloma patients.
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PMID:Interleukin-4 and tumour necrosis factor-alpha produce non isotype specific partial differentiation of peripheral blood B-cells in myeloma. 951 9

The aim of our study was to test if dendritic cells contain the KSHV genome. CD34+ peripheral blood progenitor cells (PBPC) and bone marrow mononuclear cells were cultured in X-VIVO 15 medium supplemented with GM-CSF and TNF-alpha in gas-permeable containers. Dendritic cells were identified morphologically and immunophenotypically. The KSHV genome was not identified in any of the cases using a nested primer PCR approach. Serological analysis corroborated the molecular findings: no antibodies for KSHV were found in any of the multiple myeloma patients. These data are of importance when considering use of DC for therapeutic approaches in multiple myeloma.
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PMID:Dendritic cells derived from bone marrow and CD34+ selected blood progenitor cells of myeloma patients, cultured in serum-free media, do not contain the Kaposi sarcoma herpesvirus genome. 975 67

Recombinant adenovirus (AdV) vectors are highly efficient at in vitro and in vivo gene delivery. VKCK is a murine myeloma cell line expressing the light chain of the fusion protein RM4/tumor necrosis factor (TNF)-alpha. The in vitro transfection of VKCK cells with the AdV AdV5LacZ, which contains the marker gene beta-galactosidase, can reach a maximal 75% at a multiplicity of infection of 1000. Intratumoral injections of AdV5LacZ (2 x 10(9) plaque-forming units) resulted in substantial gene transfer in nearly 50% of VKCK tumors. The AdV pLpA/M4-TNF-alpha, which contains a fused gene M4-TNF-alpha that codes for the heavy chain of fusion protein RM4/TNF-alpha, was constructed. After the in vitro transfection of pLpA/M4-TNF-alpha at a multiplicity of infection of 1000, transfected VKCK cells showed significant secretion of RM4/TNF-alpha (36 ng/mL/10(6) cells) containing the functional TNF-alpha moiety in tissue culture. The secretion peaks at day 3 and is diminished at day 6 following the viral infection. These transfected VKCK cells also became more immunogenic with enhanced expression of major histocompatibility complex class I antigen. Intratumoral injections of 2 x 10(9) plaque-forming units of pLpA/M4-TNF-alpha virus with a repeated booster resulted in significant VKCK tumor regression in immune-competent mice, but not in athymic nude mice with a mean tumor weight of 0.07 g that were compared with 1.58 g and 1.70 g for tumors injected with AdV5LacZ and phosphate-buffered saline, respectively (P < .01). The tumor regression also results in protective immunity against a second challenge with parental tumor cells, which is mainly mediated by VKCK tumor-specific CD8+ T cells. These results indicate that AdV-mediated cytokine gene therapy may be a useful approach in the clinical management of solid human tumors.
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PMID:Intratumoral vaccination of adenoviruses expressing fusion protein RM4/tumor necrosis factor (TNF)-alpha induces significant tumor regression. 991 92


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