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)

Modulation of the expression of P-glycoprotein, a plasma membrane protein associated with multidrug resistance, was examined in drug-sensitive and drug-resistant tumor cells treated with leukoregulin, a M(r) 50,000 cytokine from human lymphocytes that rapidly permeabilizes the plasma membrane of many tumor cells facilitating the uptake of doxorubicin and other tumor-inhibitory antibiotics. P-glycoprotein expression was measured flow cytometrically by the binding of C219 or MRK16 monoclonal antibody to multidrug-sensitive human K562 erythroleukemia and 8226/S myeloma cells, compared to multidrug-resistant 8226/DOX40 myeloma cells. Cells were treated for up to 2 h with up to 80 units of leukoregulin/ml or one of a variety of unrelated cytokines including interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, colony-stimulating factor, macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, gamma-interferon, alpha-interferon, epidermal growth factor, platelet-derived growth factor AA, platelet-derived growth factor BB, insulin-like growth factor I, insulin-like growth factor II, fibroblast growth factor, or transforming growth factor beta. Leukoregulin caused a concentration-dependent decrease in P-glycoprotein expression; however, P-glycoprotein expression was unaffected by the other cytokines (< 12% decrease in expression). Leukoregulin-induced membrane permeabilization, determined flow cytometrically by intracellular fluorescein efflux, and decreased P-glycoprotein expression occurred simultaneously within 15 min in drug-sensitive and -resistant cells. Enhanced doxorubicin uptake, measured flow cytometrically by doxorubicin influx, was also present within 15 min. Leukoregulin enhancement of doxorubicin uptake and increased membrane permeability varied directly with the decrease in P-glycoprotein expression. Leukoregulin in combination with doxorubicin enhanced the inhibition of cell proliferation in 8226/DOX40 multidrug-resistant cells over expressing P-glycoprotein. In contrast, combined treatment of HL-60/MX2 multidrug-resistant human promyelocytic leukemia cells that do not overexpress P-glycoprotein in association with their multidrug resistance resulted in no greater growth inhibition than observed with HL-60/MX2 cells treated with doxorubicin alone. This is the first demonstration that a naturally occurring macromolecule with anticancer activities can modulate the expression of P-glycoprotein concomitant with enhanced drug uptake and inhibition of cell proliferation.
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PMID:Decreased P-glycoprotein expression in multidrug-sensitive and -resistant human myeloma cells induced by the cytokine leukoregulin. 135 22

Leukemia inhibitory factor (LIF) is known to exhibit multiple functions by regulating the growth and differentiation of multiple normal cell types as well as malignant cells. To have a better understanding of the role of LIF, it is important to determine the level of LIF in various biological samples by developing an easy, sensitive and LIF specific assay. In this study, we have established a double monoclonal antibody (mAb) based ELISA. Four hybridoma cell lines (D3.14.1, D4.16.9, D25.1.4 and D62.3.2) secreting murine monoclonal antibodies (mAbs) against recombinant human leukemia inhibitory factor (rHuLIF) were produced by immunization of BALB/c mice with rHuLIF and by fusing immune spleen cells with P3X63Ag8U.1 myeloma cells. These mAbs each belong to the IgG1 isotype and have unique isoelectrofocusing point patterns. All four mAbs were shown to have high affinities for rHuLIF (Kd = 7 x 10(-10) to 6 x 10(-11) M) and were able to recognize the native as well as the reduced rHuLIF in an immunoblotting assay. All these mAbs showed no cross-reactivities to IL-1, IL-3, IL-6, TNF-alpha, GCSF and GMCSF. MAb D3.14.1 showed a weak binding to Oncostatin M but not to rMuLIF whereas the other three mAbs D4.16.9, D25.1.4 and D62.3.2 showed cross-reactivity to rMuLIF but not to Oncostatin M. Data obtained from a competitive binding enzyme-linked immunosorbent assay (ELISA) suggested that these four mAbs recognized different epitopes on rHuLIF. Using mAb D4.16.9 as coat antibody and horseradish peroxidase (HRP) conjugated mAb D3.14.1 as the conjugate antibody we established a double mAb based ELISA specific for human LIF which could detect as little as 100 pg/ml and 10 pg/ml of rHuLIF in the absence and in the presence of the ELAST ELISA amplification system, respectively. The addition of serum had very minimal effect on this ELISA.
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PMID:Detection of human leukemia inhibitory factor by monoclonal antibody based ELISA. 138 38

Functional pleiotropy and redundancy are characteristic features of cytokines. Interleukin 6 (IL-6) is a typical example: IL-6 induces cellular differentiation or expression of tissue-specific genes; it is involved in processes such as antibody production in B cells, acute-phase protein synthesis in hepatocytes, megakaryocyte maturation, cytotoxic T cell differentiation, and neural differentiation of PC12 (pheochromocytoma) cells. It promotes growth of myeloma/plasmacytoma cells, T cells, keratinocytes and renal mesangial cells, and it inhibits growth of myeloid leukaemic cell lines and certain carcinoma cell lines. The IL-6 receptor consists of two polypeptide chains, a ligand-binding chain (IL-6R) and a non-ligand-binding, signal-transducing chain (gp130). Interaction of IL-6 with IL-6R triggers the association of gp130 and IL-6R, and the signal can be transduced through gp130. Association of gp130 with IL-6R is involved in the formation of high affinity binding sites. This two-chain model has been shown to be applicable to receptor systems for several other cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-5 and nerve growth factor (NGF). The pleiotropy and redundancy of cytokines may be explained on the basis of this unique receptor system.
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PMID:The molecular biology of interleukin 6 and its receptor. 142 18

Multiple myeloma still remains a fatal disease. However, in the last months new biological and clinical informations have been provided about this disease. In particular, the immunophenotype of myeloma cells seems indicate, in some patients, a clonal involvement of a stem cell in the pathogenesis of mieloma. Moreover, new biological insights concerning the cytokine network, have revealed a probable effect of some cytokines, such as IL6, IL3, IL4. Finally, new insights in the biology of multiple myeloma have been provided by studies of molecular biology and flow cytometry. As for therapy, the best conventional induction treatment still remains to be defined. In the last years, the increased use of alpha Interferon and new therapeutic modalities, such as transplantation procedures in multiple myeloma, open new hopes toward a cure of this disease. Therefore, in the future a better knowledge of the multiple myeloma biology, associated with a wider use of new effective therapeutic approaches will certainly improve the natural course of this disease.
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PMID:[Recent biological and therapeutic advances in multiple myeloma]. 143 22

Peripheral blood cells of a patient with diffuse large cell non-Hodgkin's lymphoma presenting with hypereosinophilia were used to establish an EBV negative lymphoma cell line termed OCI-Ly17. Cells of the line stained positive for CD2 and CD5 determinants and demonstrated rearrangement of the T-cell receptor beta chain. The immunoglobulin heavy chain gene was found to be in germ line configuration. Northern blot studies using probes for IL-1 alpha, IL-3, IL-4, IL-5, IL-6, and GM-CSF showed message for IL-5 and IL-6. Supernatants of the cell line were evaluated on normal non-adherent, E-rosette depleted bone marrow cells to determine the presence of growth promoting activities for clonogenic eosinophilic progenitors. Eosinophilic colonies were observed. Their frequency depended upon the amount of supernatant added to the cultures. The growth promoting activity in the supernatant was reduced in a dose dependent manner by preincubation with increasing concentrations of anti-IL-5 antibodies. The supernatants of the cell line were also tested on the IL-6 sensitive human myeloma line OCI-My4 and myeloma colonies grew in response. This stimulatory activity within the supernatant was neutralized by addition of increasing concentrations of anti-IL-6 antibodies. Although producing IL-5 and IL-6 constitutively, the lymphoma line did not increase proliferation in response to either interleukin, nor did it show a reduced proliferative rate when antibodies to IL-5 or IL-6 were added to the cultures.
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PMID:Constitutive production of the interleukins IL-5 and IL-6 by the lymphoma cell line OCI-Ly 17 derived from a patient with malignant lymphoma and hypereosinophilia. 149 76

Phenotypic analysis of myeloma cells has had a major impact on our understanding of the development of the disease. Heterogeneity in the expression of lineage- and differentiation-associated antigens has helped delineate a circulating clonal premyeloma cell compartment coexpressing CD19 and CD11b. These cells can be stimulated in vitro to proliferate and differentiate into the mature myeloma cells. Other studies have demonstrated the involvement of very early bone marrow B lymphocytes, which could be differentiated into myeloma cells through a CD10-positive intermediate stage. These data suggest that myeloma originates in the bone marrow and is mobilized through the circulation to and from extramedullary sites, probably lymph nodes, which are required for their development. Subsequently, these cells return to the bone marrow or soft-tissue sites, using adhesion molecules for homing to sites that can provide the stimuli for expansion and maturation. Development of myeloma and disease manifestation are governed by a network of cytokines. Among the cytokines, IL-6 has been promoted as the major myeloma growth factor. Recent findings indicate that, whereas myeloma cells have the ability to express both the IL-6 and its receptor gene, their ability to respond to the cytokine is minimal. The requirement in vitro for both IL-3 and IL-6 for the stimulation of premyeloma cell proliferation and differentiation suggests a role for IL-6 in affecting differentiation of myeloma progenitors and the involvement of an earlier hematopoietic progenitor. Frequent association with myeloid dysplasia and neoplasia and expression of multiple hematopoietic lineage-associated markers forward the hypothesis that myeloma originates in a hematopoietic stem cell.
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PMID:Myeloma phenotype: clues to disease origin and manifestation. 158 72

In vitro data allow presentation of a plausible scenario for the in vivo growth, progression, and dissemination of human multiple myeloma (MM) that involves the interactions between the monoclonal B-cell clone and the bone marrow (BM) microenvironment. A large series of adhesion and extracellular matrix molecules allow trapping of circulating plasma cell precursors within the BM, and a battery of locally released cytokines promote their growth and final differentiation. Malignant B cells establish close contacts with BM stromal cells and release a host of cytokines that recruit and activate BM stromal cells and also T lymphocytes to produce other cytokines. All these cytokines might conceivably act in concert in a self-perpetuating mechanism of mutual help between malignant plasma cells and BM stromal cells to favor the progressive expansion of the malignant clone through a sort of an "avalanche effect." Also, most cytokines produced by malignant B cells, stromal cells, and activated T lymphocytes, including IL-1 beta, TNF-beta, M-CSF, IL-3, and IL-6, have osteoclast-activating properties, thus explaining why the expansion of the B-cell clone is matched by the activation and numeric increase of osteoclasts.
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PMID:In vitro growth of human multiple myeloma: implications for biology and therapy. 158 73

In multiple myeloma (MM), an overproduction of IL-6, indicated by increased plasma C-reactive protein levels, is found in 37% of MM patients at diagnosis and is associated with disease aggressiveness, myeloma-cell proliferation, and poor prognosis. IL-6 is produced by the tumoral environment mainly and not by myeloma cells themselves. IL-6 is a major growth factor for malignant plasmablastic cells in vitro, and it is possible to reproducibly obtain IL-6-dependent myeloma-cell lines. Moreover, anti-IL-6 therapies in patients with terminal disease block myeloma-cell proliferation in vivo. The myeloma-cell growth factor activity of IL-6 is probably the consequence of IL-6 being a growth factor for normal plasmablastic cells. Hematopoietic cytokines (GM-CSF, IL-3, IL-5, G-CSF) synergize with IL-6 to support myeloma-cell proliferation. IFN-alpha and TNF induce an autocrine production of IL-6 in myeloma-cell lines and make possible the autonomous growth of these cell lines. On the contrary, IFN-gamma completely inhibits the IL-6-mediated myeloma-cell proliferation. The identification of some major cytokines involved in the control of the myeloma clone has immediate therapeutic implications, because some of these cytokines are, or might be, used in the treatment of patients with MM.
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PMID:Cytokine network in human multiple myeloma. 158 74

We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation, terminal differentiation, and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast-like elements, interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+, produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta, and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures, monoclonal B lymphocytes and plasma cells, derived from PBMC, developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes, plasma cells, and osteoclasts and the in vivo dissemination of MM.
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PMID:'Role of bone marrow stromal cells in the growth of human multiple myeloma. 167 30

The controversial role of interleukin-6 (IL-6) as an auto- or paracrine growth factor for human multiple myeloma (MM) cells was studied using a panel of six well characterized feeder-cell dependent and independent MM cell lines as models. With respect to the effect of IL-6 on growth and survival, three types of lines were found: (1) U-1958, dependent on IL-6 both for growth and survival; (2) U-1996, dependent on IL-6 for growth but not survival; and (3) U-266-1984, Fravel, L363, and Karpas 707, independent of IL-6. Feeder-cell supernatants were as efficient as feeder-cell monolayers in stimulating growth and contained IL-6 as the only growth promoting activity. IL-6 was growth stimulatory and sustained the growth of U-1958 only when the medium contained fetal calf serum. The nature of the serum factor(s) is unknown, but it was excluded to be the IL-6 carrier protein a2-macroglobulin. IL-1, IL-2, IL-3, TNF-alpha, GM-CSF, IGF-1, and insulin were neither co-stimulatory with IL-6 nor stimulated growth on their own. Only U-266-1984 expressed IL-6 mRNA. IL-6 receptor mRNA was expressed in all lines except the L363 and Fravel. We conclude that the response to IL-6 is heterogeneous among the MM lines and that IL-6 acts as a paracrine growth factor for two of six lines. In a third line, U-266-1984, the IL-6 mRNA expression suggests the possibility of an autocrine growth stimulation.
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PMID:Heterogeneity in response to interleukin 6 (IL-6), expression of IL-6 and IL-6 receptor mRNA in a panel of established human multiple myeloma cell lines. 170 69


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