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

368 1- to 5-year-old mink of wild-type or black genetic background were infected with Aleutian disease virus (ADV) naturally or using virus-containing immune complexes or purified virus. Thirty of the mink were immunized with dinitrophenol-conjugated ovalbumin (DNP-OA) before and during infection. Blood samples were taken at monthly intervals. We found that weak (and transient) monoclonal or oligoclonal immunoglobulin components were present in the plasma or serum approximately 1 month after infection, as judged by zone electrophoresis. In a few cases, we found quite stable myeloma-like hypergammaglobulinemia, which usually occurs much later in the infection. All sera with monoclonal immunoglobulin components and most of the sera with immunoglobulins of restricted heterogeneity were analysed by crossed serum line immunoelectrophoresis. In all cases, the distinct immunoglobulins were found to have antibody activity to ADV proteins. In the few sera from DNP-OA-immunized mink showing restricted immunoglobulin heterogeneity, this was also the case. The findings from the study imply that ADV-specific B lymphocytes are probably the primary targets for ADV. The resulting ADV replication introduces a "pseudo-transformation" stage, so that the infected B lymphocytes proliferate and differentiate to an extreme degree. The mechanism behind this B-cell pseudotransformation ability of ADV is a puzzle. It may, however, be important, that the p75/85 structural polypeptides of ADV contain an amino acid sequence almost identical to the GTP-binding pocket of the Ras oncogene.
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PMID:Virus-specific B-lymphocytes are probably the primary targets for Aleutian disease virus. 165 Oct 29

A novel human myeloma cell line, OH-2, was established from pleural fluid of a myeloma patient in end stage of the disease. Effects of cytokines on proliferation were analyzed by measuring uptake of 3H-thymidine. Cell surface antigens were detected by flow cytometry. The cell line is dependent on IL-6 for growth and proliferates in response to TNF. There is synergy between the stimulatory response of TNF and IL-6. The cells express both the p55 and p75 TNF receptors. Neutralizing anti-IL-6 did not inhibit TNF-mediated proliferation, showing that TNF acts through a pathway that is independent of IL-6. TNF was more potent than IL-6 in stimulating the growth of primary myeloma cultures (> 99% pure) from the same patient (OH-2-PC), indicating that TNF in selected myeloma patients has a growth-promoting effect equal to IL-6. OH-2 cells produce and secrete monoclonal IgG-kappa.
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PMID:TNF and IL-6 are potent growth factors for OH-2, a novel human myeloma cell line. 806 95

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

We wanted to study the role of the two TNF receptors (TNFR) in mediating proliferation and nuclear transcription factor kappa-B (NF-kappa B) activation in the human myeloma cell line OH-2. Agonistic antibodies to either of the TNFRs were able to induce proliferation in OH-2 cells, while only antibodies to the p55 TNFR could activate the NF-kappa B. TNF was 100-1000-fold more potent than LT alpha in activation of NF-kappa B and in induction of proliferation in OH-2 cells. Only a 2-fold difference between TNF and LT alpha in affinity for the TNFRs was detected, indicating that the difference in the specific activities of the cytokines can not be explained by different binding affinities. Antagonistic mAbs to either the p55 or p75 TNFR blocked the binding of both cytokines to the cells and significantly inhibited proliferation induced by TNF. On the other hand, only the p55 TNFR mAb was capable of inhibiting the proliferative effect of LT alpha. The p55 mAb 44E potentiated the proliferation induced by LT alpha, but did not affect the TNF-mediated proliferation. The data lead to the following conclusions: (1) both TNFR species trigger proliferation of OH-2 cells, whereas only the p55 TNFR activates the NF-kappa B; (2) TNF signals through both TNFR, whereas LT alpha mediates its signal through the p55 TNFR only; (3) activation of the p55 TNFR by LT alpha is not optimal, but can be facilitated by co-stimulating the receptor with the mAb 44E.
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PMID:The role of the two TNF receptors in proliferation, NF-kappa B activation and discrimination between TNF and LT alpha signalling in the human myeloma cell line OH-2. 881 39

We have studied tissue expression of the cytokine receptors using a high sensitivity biotin-streptavidin system on cryostat sections. We used a panel of monoclonal antibodies from the 6th International Workshop on Human Leukocyte Differentiation Antigens, namely CD25 (IL-2R alpha), CD95 (FAS antigen), CD116 (GM CSFR), CD117 (SCFR), CD120 alpha (TNFR I), CD120b (TNFR II), CD121a (IL-1R I), CDw123 (IL-3R), CD124 (IL-4R), CD126 (IL-6R), CD127 (IL-7R), CDw128 (IL-8R), CD130 (gpl130), CD131 (IL-3R), CD132 (IL-2R gamma), CD134 (OC-40), CD135 (FLT3/FLK2). Examined tissues (lymph nodes and spleens) were obtained from 12 patients with folicular non-Hodgkin's lymphoma, periferal T non-Hodgkin's lymphoma, B lymphoma, myeloma, Hodgkin's disease, two cases of T cell rich B-lymphoma, autoimmune haemolytic anemia and two cases of rudimentary trombocytopenic purpura. Our results indicate that immunohistological technology using native tissues on cryostat sections, monoclonal antibodies and the visualisation with biotin-streptavidin is a particularly suitable supplementary staining procedure for detection of the cytokine receptors in tissues.
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PMID:[Immunohistochemical detection of cytokine receptors on cryostat tissue sections]. 1037 62

Tumor necrosis factor (TNF)-alpha is a major effector and regulatory cytokine with a pleiotropic role in the pathogenesis of several immune-regulated diseases, including graft versus host disease (GVHD) and hematologic malignancies, such as multiple myeloma (MM), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Curative treatment for the above diseases are not currently available for most patients. Therapeutic approaches inactivating or blocking TNF-alpha are being evaluated in clinical trials. This review describes the development of the soluble TNF-alpha receptor (p75 TNF-R: Fc; etanercept) and other agents inactivating or blocking TNF-alpha in the management of patients with hematologic malignancies. The satisfactory safety profile of etanercept--as demonstrated in patients with autoimmune diseases--has been confirmed in patients with hematologic malignancies and GVHD. Studies to assess whether etanercept, either as a single agent or in combination with cytotoxic and/or immune therapy, may increase response rates and/or survival in patients with MM, MDS, AML and other hematologic malignancies are now warranted.
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PMID:TNF-alpha targeted therapeutic approaches in patients with hematologic malignancies. 1211 51

Elevated tumor necrosis factor (TNF)-alpha levels are associated with poor prognosis in patients with multiple myeloma (MM). Enbrel is a TNF antagonist fusion protein consisting of the extracellular, ligand-binding domain of the human p75 TNF receptor linked to the Fc portion of human IgG1. Ten patients with refractory MM were treated with Enbrel 25mg s.c twice weekly for a minimum of eight median age was 63 years (range, 43-76). The total number of Enbrel doses was 191 (median 16; range, 3-55). TNF alpha plasma levels increased significantly during treatment with Enbrel. No objective response occurred. Acceleration of disease occurred in four patients. While well-tolerated, Enbrel did not have anti-myeloma activity as administered on this study.
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PMID:Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment. 1262 Feb 87

Etanercept is a commercially available pharmaceutical protein approved for treatment of rheumatoid arthritis, RA. Given subcutaneously, etanercept binds and inactivates soluble tumor necrosis factor-alpha, TNF. Etanercept has a good safety record and is of benefit in lowering pain, inflammation, and joint destruction in RA. RA is mediated by many factors, TNF among them. Malignant myeloma, MM, is a malignant clonal expansion of a post-germinal center B lymphocyte. Since TNF is a necessary growth factor for expansion and maintenance of MM cells, and etanercept binds soluble TNF and is of clinical benefit in RA, etanercept was tried experimentally in MM. Contrary to expectations, etanercept resulted in increased levels of TNF and possibly shortened survival. This paper presents an hypothesis of how this happened. There are two cognate receptors for TNF, termed R1 and R2 and two forms of TNF, soluble and transmembrane. Soluble TNF has greater affinity for TNF-R1 than for TNF-R2. Transmembrane TNF has equal affinity for the two receptors. Since TNF-R2 signaling tends to be more anti-apoptotic and activating of nuclear factor kappa B, NFkB, than is TNF-R1, and TNF-R1 tends to be more pro-apoptotic than is TNF-R2, by inactivating soluble TNF while leaving transmembrane TNF signaling relatively unchanged, etanercept changed the balance in TNF signaling from TNF-R1 towards TNF-R2 weighting. Anti-apoptosis and TNF synthesis would have been up-regulated by that shift. Early data indicates that the common generic antidepressant bupropion may ameliorate Crohn's disease course by down regulating TNF synthesis, maybe it will slow the course of MM as well.
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PMID:Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: new insights into the biology of TNF-alpha giving new treatment opportunities--the role of bupropion. 1596 26

Cytokines (interleukins, chemokines, and some growth factors) play an important role in cancer, metabolic disorders, autoimmune disorders and inflammatory diseases, such as rheumatoid arthritis, asthma, Crohn's disease, psoriasis, multiple sclerosis and asthma. Cytokine-based drugs and anticytokine therapies are an increasingly important class of drugs in the treatment and management of many diseases. Interferons are being used to treat viral diseases and cancers. Anti-tissue necrosis factor therapies, such as Enbrel (etanercept; Immunex Corp) and Remicade (infliximab; Centocor) have demonstrated clinical efficacy in rheumatoid arthritis and Crohn's disease. In addition, thalidomide (Celgene) is being used to treat erythema nodosum in leprosy, cancers (multiple myeloma and colon cancer) and autoimmune diseases. This conference focused on new developments in basic research, drug discovery and clinical development of cytokine-based drugs.
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PMID:Cytokines as drug targets. 1601 67

Brain-derived neurotrophic factor (BDNF), a major neuronal growth factor, is also known to exert an antiapoptotic effect in myeloma cells. Whereas BDNF secretion was described in B lymphocytes, the ability of B cells to produce sortilin, its transport protein, was not previously reported. We studied BDNF production and the expression of its receptors, tyrosine protein kinase receptor B and p75 neurotrophin receptor in the human pre-B, mature, and plasmacytic malignant B cell lines under normal and stress culture conditions (serum deprivation, Fas activation, or their combination). BDNF secretion was enhanced by serum deprivation and exerted an antiapoptotic effect, as demonstrated by neutralization experiments with antagonistic Ab. The precursor form, pro-BDNF, also secreted by B cells, decreases under stress conditions in contrast to BDNF production. Stress conditions induced the membranous expression of p75 neurotrophin receptor and tyrosine protein kinase receptor B, maximal in mature B cells, contrasting with the sequestration of both receptors in normal culture. By blocking Ab and small interfering RNA, we evidenced that BDNF production and its survival function are depending on sortilin, a protein regulating neurotrophin transport in neurons, which was not previously described in B cells. Therefore, in mature B cell lines, an autocrine BDNF production is up-regulated by stress culture conditions and exerts a modulation of apoptosis through the sortilin pathway. This could be of importance to elucidate certain drug resistances of malignant B cells. In addition, primary B lymphocytes contained sortilin and produced BDNF after mitogenic activation, which suggests that sortilin and BDNF might be implicated in the survival and activation of normal B cells also.
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PMID:Role of endogenous brain-derived neurotrophic factor and sortilin in B cell survival. 1871 73


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