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)

In order to assess cytokine-producing cells at the single cell level, the cytokine-specific ELISPOT assay has proven to be an important and sensitive method. The purpose of this study was to adapt this method to elucidate individual cells producing murine IL-2, IL-4 or IL-6. In order to establish these cytokine-specific ELISPOT assays, IL-2-, IL-4- and IL-6-specific cDNA transfected myeloma cell lines, e.g., X63-Ag8-653 X2, X63-Ag8-653 X4 and X63-Ag8-653 X6, respectively, were used as specific cytokine-producing cells. In the IL-2 ELISPOT assay, the coating reagent, monoclonal antibody (mAb) rat IgG2a anti-mouse IL-2 (CR #40014) was used while rabbit IgG polyclonal anti-mouse IL-2 was employed for detection of IL-2 spot forming cells (SFC). The mAbs anti-mouse IL-4, BVD4-1D11 and BVD6-24G2 were selected as capture and detection antibodies for enumeration of IL-4 SFC. For the IL-6 ELISPOT assay, anti-mouse IL-6 (MP5-20F3) mAb was used for coating and MP5-32C11 mAb was used for detection of IL-6 SFC. When IL-2 producing X63-Ag8-653 X2 cells were subjected to these three different ELISPOT assays, IL-2-specific SFC were only noted with the IL-2 ELISPOT system. In the case of IL-4 SFC, only X63-Ag8-653 X4 cells formed specific spots using the tandem of BVD4-1D11 and BVD6-24G2 mAbs. IL-6-specific spots developed in MP5-20F3 mAb pre-coated wells containing X63-Ag8-653 X6 cells, when developed with mAb anti-IL-6 (MP5-32C11). Addition of cycloheximide (50 micrograms/ml) inhibited formation of IL-2, IL-4 and IL-6 SFC by approximately 90%. When an unrelated mAb was used as detection antibody in these three different cytokine-specific ELISPOT assays, IL-2-, IL-4- and IL-6-specific SFC were not detected. Further, when concanavalin A stimulated T cells from Peyer's patch of normal mice were subjected to the respective cytokine-specific ELISPOT assay, IL-2, IL-4 and IL-6 SFC were enumerated. These results have shown that cytokine-specific IL-2, IL-4 and IL-6 ELISPOT assays have now been established and will allow analysis of the frequency of cytokine-secreting cells at the single cell level.
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PMID:Cytokine-specific ELISPOT assay. Single cell analysis of IL-2, IL-4 and IL-6 producing cells. 845 5

The uniformly fatal plasma cell malignancy, multiple myeloma (MM), currently represents 10-15% of hematologic neoplasms in the USA and has been steadily increasing in incidence for several decades. Therapeutic alternatives have lagged significantly behind insights into the biology and pathogenesis of this entity. Traditionally felt to be a neoplasm of fully differentiated plasma cells, evidence has been mounting that the self renewing population consist of cells derived from a much earlier compartment; perhaps prior to B-cell lineage commitment or even at the level of an earlier 'stem cell'. Bcl-2 protein overexpression has been almost uniformly seen in both clinical myeloma specimens as well as in myeloma cell lines. The failure to consistently identify the t(14;18) translocation, normally found in follicular lymphomas and characteristically associated with overexpression of bcl-2, implies a unique mechanism in MM. A number of cytokines, including TNF alpha, IL-1 and IL-6 have been found to play a central role not only in the biology of the malignant clone but also in the bony and other systemic manifestations of this disease. Since both IL-6 and bcl-2 protein have been shown to prevent programmed cell death, this may be the unifying event in MM. Standard therapy for MM has been an alkylating agent and corticosteroid. Combination chemotherapy provides more prompt palliation but no clear survival advantage. In advanced stages, adriamycin may offer some survival advantage. High dose chemotherapy with or without stem cell support offers a potentially curative therapeutic approach. New interventions directed at the complex cytokine networks pertinent to the pathogenesis of MM are an exciting new area of investigation. Identification of new prognostic parameters as well as new active agents remains the central theme in clinical myeloma research.
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PMID:Biology and treatment of multiple myeloma. 846 29

We have investigated which of the cytokines that are relevant in the in vitro growth of multiple myeloma (MM) malignant plasma cells are actually produced in vivo by MM patients. To this end, we have measured the levels of IL-1 beta, IL-3, IL-4, IL-6, IL-7, IL-8 and tumour necrosis factor-alpha (TNF-alpha) both in sera and in the supernatant of bone marrow (BM) stromal cell cultures from patients with MM and monoclonal gammopathy of undetermined significance (MGUS). The significance of our findings is three-fold. First, IL-6 and IL-8 are produced by MM BM stromal cells, while IL-1 beta, TNF-alpha, IL-4 and IL-7 are not. Second, IL-3 is the only cytokine consistently raised in serum samples: we have also detected low levels of serum IL-6 in a minority of cases, usually in advanced stage of the disease. Third, MM BM stromal cells are active IL-6 and IL-8 producers, while both normal and MGUS BM stromal cells are low producers, thus suggesting that in the BM of MM a number of environmental cells, that would normally be quiescent, are instead activated and that, in MM, activated BM stromal cells play an active role in supporting the progressive expansion of the B cell clone.
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PMID:Cytokines involved in the progression of multiple myeloma. 846 62

The overall effects of corticosteroids on the skeleton are dependent on many factors including dose, duration of exposure to the steroid, steroid type and species. Some effects are indirect and are brought about by changes in, for example, parathyroid hormone secretion and intestinal calcium absorption, while others may result from cellular responses within the microenvironment of bone itself. Explants of trabecular bone are commonly used to study glucocorticoid effects in vitro, though it is often difficult to be certain that in vitro results directly reflect in vivo activity. Corticosteroids are dual inhibitors of cyclo-oxygenase and lipo-oxygenase, and may exert effects via inhibition of eicosanoid synthesis. They can also inhibit synthesis of cytokines, such as interleukin-1, which stimulate bone resorption and remodelling, by monocytes and macrophages. The production of cytokines and growth factors by bone cells themselves and the expression of their receptors may also be influenced by corticosteroids. Examples of corticosteroid-induced inhibition of synthesis include tumour necrosis factor and interleukin-6, and such effects may be important in explaining therapeutic actions of corticosteroids (e.g. in myeloma). Although it is not yet clear why different glucocorticoids have different effects, a number of factors determine the overall effect of a steroid. These include steroid metabolism and tissue distribution, selective effects on cytokine production, and tissue differences in gene transcription.
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PMID:Cellular regulatory mechanisms that may underlie the effects of corticosteroids on bone. 849 80

Interleukin-6 (IL-6) has been suggested to play a major role in multiple myeloma. To investigate the source and target cells of IL-6 activity in multiple myeloma, expression of the cytokine and its receptor genes by myeloma plasma cells was studied. Tumor cells were sorted from bone marrow aspirates of myeloma patients using 4-parameter gating. Myeloma cells were identified as CD38high CD45negative-intermediate and by their light-scatter characteristics. Sorted cells contained only myeloma plasma cells. No contaminating cells were present as determined morphologically, by monoclonal cytoplasmic Ig analysis, and by polymerase chain reaction (PCR) amplification of marker genes. Myeloma cells from 45% of patients expressed IL-6. IL-6 receptor transcripts were found in 68% of the specimens. IL-6 gene expression correlated with expression of the IL-6 receptor gene (P < .005). Correlations observed between the expression of CD45, a protein tyrosine phosphatase expressed by B lymphocytes but not by plasma cells, and the expression of the IL-6 and IL-6-receptor genes (P < .0002 and P < .005, respectively) suggest that an autocrine IL-6 loop is functioning in myeloma in preplasma cells.
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PMID:Interleukin-6 gene expression in multiple myeloma: a characteristic of immature tumor cells. 850 73

It remains to be clarified whether IL-6 acts on the growth of human myeloma cells by an autocrine or paracrine mechanism. Even in established myeloma cell lines, the autocrine growth by IL-6 appears unusual. In the present study, we deviced a model of IL-6 autocrine growth in vitro by transfecting IL-6 cDNA into a human myeloma cell line that had a proliferative response to IL-6 but did not produce IL-6. After IL-6 transfection, the cells (S6B45) proliferated in culture media without IL-6. IL-6 production by S6B45 was demonstrated both at protein and mRNA level. The growth of S6B45 was definitely inhibited by anti-IL-6 (MH166) or anti-IL-6 receptor (PM1) monoclonal antibodies. Furthermore, S6B45 was successfully transplanted to nude mice. The transplanted tumor growth was clearly inhibited by the administration of MH166 or PM1 to the mice. The in vivo antitumor activity of these antibodies suggest a new therapeutic strategy against tumors that proliferate by an autocrine mechanism through a cytokine such as IL-6.
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PMID:[Growth characteristics of a human myeloma cell line transfected with IL-6 cDNA]. 851 Mar 28

There are only 3.3% of patients with multiple myeloma in Japan Myeloma Study Group who have lived longer than ten years. Features associated with long survival include responded well to simple treatment such as melphalan or cyclophosphamide and prednisone, short duration of treated time with long activity and prolonged unmaintained remissions. High-dose melphalan therapy, VAD chemotherapy and MCNU-VP16-melphalan combination were tried for patients relapsed with alkylating agents and the result were reported. Bone marrow transplantation and cytokine therapy for myeloma will be discussed.
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PMID:[Recent therapy for refractory myeloma]. 851 Mar 32

In clinical trials with interferon alpha 2b (IFN-alpha 2b) as maintenance therapy for multiple myeloma, the therapeutic benefit is inconclusive. Although the mechanism(s) by which IFN-alpha 2b prolongs remission in some patients is unknown, 2',5'-oligoadenylate synthetase (2,5-A synthetase) has been used as an objective indicator that IFN-alpha 2b is active in vivo. The enzyme was assayed in cytosol preparations of peripheral blood mononuclear cells (MNCs) from 111 patients who were receiving IFN-alpha 2b and 54 patients who were not, using an assay which measures the conversion of [alpha-32P]ATP to triphospho(adenylyl 2',5')adenosine. 2,5-A synthetase activity was compared with response to intensive therapy and with duration of maintenance therapy. Seventy-three per cent of patients had measurable amounts of 2,5-A synthetase during the first 6 months of maintenance therapy. This percentage decreased with longer follow-up but not significantly. There was no difference between the magnitude of enzyme induction amongst patients who were in complete remission, partial response or who had no change in disease status following intensive therapy. Peripheral blood T cells were a major source of 2,5-A synthetase activity in patients receiving the cytokine. However, both T and B cells produced the enzyme following exposure to IFN-alpha in vitro. The data show that the level of 2,5-A synthetase in patients with multiple myeloma is not indicative of clinical response to IFN-alpha 2b.
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PMID:2',5'-Oligoadenylate synthetase levels in patients with multiple myeloma receiving maintenance therapy with interferon alpha 2b do not correlate with clinical response. 851 71

By analogy with the model of pristane-induced mouse plasmacytomas, we have wondered about the putative role of prostaglandin E2 (PGE2) in the human multiple myeloma (MM) cytokine network, involving interleukin 6 (IL-6) and interleukin 1 (IL-1) as essential myeloma cell growth factors and inducing cofactors respectively. We show that PGE2 is produced in short-term cultures of bone marrow cells of patients with MM, concomitantly with both IL-6 and IL-1. Indomethacin, a potent inhibitor of cyclo-oxygenase and of PGE2 synthesis, significantly inhibits IL-6 production (but not IL-1 production) by 35% to 90% depending on the different MM patients studied and concurrently to that of PGE2. Exogenous PGE2 reverses this inhibition or even stimulates IL-6 production. An IL-1 receptor antagonist (IL-1RA) also significantly inhibits PGE2, IL-6 production and myeloma cell growth. The inhibition of IL-6 production is reversed by adding exogenous PGE2. These results show that induction of IL-6 by IL-1 is related to PGE2 in the bone marrow of patients with MM. Inhibition of PGE2 synthesis (as obtained with indomethacin and the IL-1RA) might be helpful to inhibit myeloma cell proliferation by reducing IL-1-induced endogenous IL-6 production not only in vitro (as demonstrated here) but also in vivo.
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PMID:An interleukin 1 receptor antagonist blocks the IL-1-induced IL-6 paracrine production through a prostaglandin E2-related mechanism in multiple myeloma. 852 May 8

Genetic alterations are a common feature of the malignant phenotype. Among other properties, altered genes may be responsible for invasion and metastasis, as well as for resistance to chemotherapeutic agents. Under appropriate circumstances, the products of other altered genes expressed by malignant cells may act as tumor-associated T-cell epitopes, capable of provoking antitumor immune responses. As a novel means of augmenting the immunogenicity of the gene products, unfractionated, sheared genomic DNA from various tumor cell lines (B16F1 melanoma, B16F10 melanoma, MOPC-315 plasmacytoma, C1498 lymphoma, or J558 myeloma), or from non-neoplastic liver cells of tumor-free mice, was transfected into LM cells, a mouse fibroblast cell-line (H-2k) that had been modified previously by retroviral gene transfer to secrete interleukin-2 (IL-2). The IL-2-secreting transfected cell populations were then tested for their immunogenic properties toward B16F1 (H-2b) or C1498 (H-2b) cells in syngeneic C57BL/6 mice. The antitumor responses were specific for the type of tumor from which the DNA was obtained. The survival of C57BL/6 mice injected with a mixture of viable B16F1 cells and IL-2-secreting LM cells transfected with DNA from B16F1 cells was significantly prolonged. In a similar manner, the survival of C57BL/6 mice injected with a mixture of C1498 cells and IL-2-secreting LM cells transfected with DNA from C1498 cells was prolonged as well. The immunity was mediated predominantly by CD8+ and natural killer/lymphokine-activated killer (NK/LAK) cells. These data raise the possibility that a cell line altered previously for cytokine secretion may be readily modified to provide immunologic specificity for the neoplasms of individual cancer patients.
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PMID:Interleukin-2-secreting mouse fibroblasts transfected with genomic DNA from murine neoplasms induce tumor-specific immune responses that prolong the lives of tumor-bearing mice. 852 61


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