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

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

A human multiple myeloma (MM) cell line, U-266, has developed the ability to grow independently of exogenous interleukin 6 (IL-6) during long-term cultivation in vitro. The early passage, feeder-cell dependent U-266 cell line (U-266-1970) was compared with the late passage U-266-1984 cell line with respect to response to IL-6, IL-1 beta and tumour necrosis factor alpha and expression of IL-6 and IL-6 receptor (IL-6R) mRNA and protein. The results showed that; (a) only the U-266-1970 cell line was stimulated to growth by IL-6, (b) IL-6 and IL-6R mRNA were expressed in both cell lines, (c) the level of IL-6 mRNA was increased in the U-266-1984 cell line and only this line produced IL-6 and, (d) the level of IL-6R mRNA was highest in the U-266-1984 cell line and the number of IL-6R about ten times higher than in U-266-1970. The growth of the IL-6-producing U-266-1984 cell line was inhibited by 30% by anti-IL-6R antibodies suggesting the possibility that an autocrine IL-6 loop might have developed during the long-term cultivation. In addition to many other phenotypic alterations of the U-266 cell line, having developed as a consequence of tumor progression in vitro, its growth factor requirement seems to have evolved from a dependence on IL-6 as a paracrine growth factor to a capacity for autonomous growth, dependent on autocrine IL-6 stimulation. Whether such a development also may take place in MM clones in vivo remains to be established.
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PMID:Increase in interleukin 6 (IL-6) and IL-6 receptor expression in a human multiple myeloma cell line, U-266, during long-term in vitro culture and the development of a possible autocrine IL-6 loop. 158 93

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

An IgE-binding factor(s) (IgE-BF(s] was partially purified from the supernatant of human HTLV-II carrying T-cell line MO. This IgE-BF(s) was shown to increase the IgE synthesis in the human myeloma cell line U-266, but did not affect its viability or growth. The effect of the IgE-BF(s) was dose-dependent and selective for IgE protein synthesis as beta 2-microglobulin synthesis in the U-266 and the immunoglobulin production in the U-1958 IgG-secreting human myeloma cell line were unaffected. The IgE-BF(s) increased the production of the epsilon heavy chain but not the lambda light chain production. The IgE-BF(s) was distinct from IL-1 beta, IL-3, IL-4, IL-5, IL-6, TNF-alpha, IFN-alpha, -beta, -gamma, M-CSF, and fragments of CD23.
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PMID:Enhancement of IgE synthesis in the human myeloma cell line U-266 with an IgE binding factor from a human T-cell line. 174 21

Regulatory effects of glucocorticoids (dexamethasone) on myeloma cells as well as bone resorption in multiple myeloma were investigated. Glucocorticoids significantly inhibited proliferation of myeloma cells, and decreased the messenger RNA (mRNA) expressions of interleukin-6 (IL-6) and secretory type immunoglobulin G (IgG). The inhibitory effects of glucocorticoids on myeloma cell proliferation could be due to the decreased expression of IL-6 mRNA, decreased IL-6 production, and thus suppression of autocrine growth by IL-6, which is an autocrine growth factor for myeloma cells as reported previously (Nature 332:83, 1988). Glucocorticoids also inhibited M-protein secretion by decreasing the levels of secretory type Ig mRNA. On the other hand, because IL-1 beta rather than lymphotoxin is considered to be a major osteoclast activating factor (OAF) produced by myeloma cells, and glucocorticoids decreased the expression of IL-1 beta mRNA and markedly suppressed the bone resorbing activity induced by IL-1 beta OAF in 45Ca-release bone resorption assay, it is suggestive that glucocorticoids could inhibit bone resorption induced by IL-1 beta OAF in multiple myeloma. Therefore, from these data it is concluded that glucocorticoids could be more effective chemotherapeutic agents in multiple myeloma than we expected, especially with regards to the inhibitory effects on proliferation and M-protein secretion from myeloma cells, as well as bone resorption by myeloma cells.
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PMID:Effect of glucocorticoids on the biologic activities of myeloma cells: inhibition of interleukin-1 beta osteoclast activating factor-induced bone resorption. 229 74

This study investigates the capacity of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) to induce interleukin-6 (IL-6) production in freshly isolated myeloma cells (MC) and bone marrow-derived stromal cells (MSC). Recombinant human (rh) IL-1 alpha, IL-1 beta and TNF-alpha augmented production of IL-6 in human MC. IL-6 was determined on a factor-dependent Cess cell line. This activity was completely abrogated by anti-IL-6 antibodies. Prior incubation of IL-1 alpha, IL-1 beta and TNF-alpha with their respective antibodies inactivated the ability of recombinant cytokines to stimulate the release of IL-6 from myeloma cells. IL-1 alpha, IL-1 beta and TNF-alpha enhanced 3H-TdR uptake in myeloma cells through IL-6, as antibodies to IL-6 completely abolished the DNA synthesis induced by culture supernatants of MC exposed to these cytokines. rhIL-6 reversed the inhibitory action of anti-IL-6 antibodies and reinduced DNA synthesis in MC. Next we found that IL-1 alpha, IL-1 beta and TNF-alpha induced MSC to produce IL-6. In contrast, supernatants of unstimulated MSC did not contain detectable IL-6 biologic activity. Further data demonstrated that human MC were able to induce IL-6 production in MSC. The stimulatory activities of MC appeared to be mediated through endogenously released IL-1, as the addition of antibodies towards IL-1 at the initiation of cocultures completely abrogated the IL-6 production. We conclude from our data that IL-1 and TNF-alpha may play an important role in the pathogenesis of human multiple myeloma.
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PMID:The role of interleukin-1 and tumour necrosis factor-alpha in human multiple myeloma. 234 22

Previous work with continuously cultured multiple myeloma lines suggested that cytokine production by tumor cells may mediate some of the medical complications of this disease. To further investigate this issue, we assayed freshly obtained bone marrow (BM) cells from myeloma patients for the in vitro production of cytokines and the presence of cytokine RNA. Production of cytokine protein was assessed by bioassays with the aid of specific neutralizing anticytokine antibodies. These assays detected interleukin-1 (IL-1) and tumor necrosis factor (TNF) secretion by myeloma BM cells, which was significantly greater than secretion from similarly processed BM cells of control individuals. In contrast, lymphotoxin and interleukin-2 (IL-2) production could not be detected. The levels of IL-1 and TNF produced in vitro peaked at 24 hours of culture and correlated with stage and the presence (or absence) of extensive osteolytic bone disease. Northern blot analysis demonstrated the presence of IL-1 beta and TNF RNA in uncultured myeloma BM cells but no detectable IL-1 alpha or lymphotoxin RNA. In addition, the amount of cytokine RNA correlated with protein production, being significantly greater in patients' BM cells than in control marrow. These data suggest a role for IL-1 beta and/or TNF in the pathophysiology of multiple myeloma and argue against a role for lymphotoxin or IL-2.
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PMID:Production of cytokines by bone marrow cells obtained from patients with multiple myeloma. 247 82

A number of antigens (Ags) are expressed on normal and malignant terminal B (plasma) cells, including plasma-cell, earlier B-cell, and non-B cell-Ags. These Ags, coupled with indirect and dual fluorochrome labelling techniques, permit characterization of normal and malignant in vitro and in vivo terminal B-cell differentiation. The majority (90%) of B cells within spleen bear Bl and lack PCA-1 Ags. As B cells differentiate to pokeweed mitogen in vitro, immunoglobulin (Ig) secretion precedes the appearance of cell surface PCA-1 and plasmacytoid morphology. Dual fluorescence cell sorting permits characterization of in vivo B-cell differentiation: Bl + PCA-1 + cells are more "differentiated" since they are more prevalent in lymph node than spleen, exhibit plasmacytoid morphology and maximal Ig secretion, and no longer respond to triggers of B-cell proliferation; in contrast, Bl + PCA-1-cells are lymphoid in morphology and may respond to triggers of B-cell proliferation as "resting" B cells. Similar studies of myeloma cells demonstrated that they may also include cells expressing plasma-cell, earlier B, and non-B cell Ags. Although they neither proliferated nor secreted Ig in vitro to G/M-CSF, G-CSF, M-CSF, IL-1, IL-1B, IL-2, or IL-4, proliferation without Ig secretion (Stimulation Index greater than or equal to 3.0) was induced to IL-6 in 6 of 10 patients (pts); to IL-3 (2 pts) and to IL-5 (2 pts).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenotypic and functional characterization of normal and malignant terminal B (plasma) cells. 262 90

Tumor cells were isolated from the bone marrow of seven patients with multiple myeloma and from the peripheral blood of three patients with plasma cell leukemia using Ficoll-Hypaque (FH) density sedimentation followed by immune rosette depletion of T, myeloid, monocytoid, and natural killer (NK) cells. Enrichment to greater than or equal to 93% plasma cells was confirmed with Wright's-Giemsa staining, with intracytoplasmic immunoglobulin staining, and with staining using monoclonal antibodies (MoAbs) directed at B, T, myeloid, monocytoid, and myeloma antigens in indirect immunofluorescence assays. Myeloma cells neither proliferated nor secreted Ig in response to G/M-CSF, G-CSF, M-CSF, interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), or interleukin-4 (IL-4). Significant proliferation (SI greater than or equal to 3.0) was induced by interleukin-6 (IL-6) in six of ten patients (SI of 31 and 43 in two cases); and to interleukin-3 (IL-3) and interleukin-5 (IL-5), independently, in two patients each. Peak proliferation to IL-5 or IL-6 and to IL-3 occurred in cells pulsed with 3[H] thymidine at 24 and 48 hours, respectively; and proliferation to combinations of factors did not exceed that noted to IL-6 alone; Ig secretion was not documented under any culture conditions. Three myeloma-derived cell lines similarly studied demonstrated variable responses. The heterogeneity in the in vitro responses of myeloma cells and derived cell lines to exogenous growth factors enhances our understanding of abnormal plasma cell growth and may yield insight into the pathophysiology of plasma cell dyscrasias.
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PMID:Response patterns of purified myeloma cells to hematopoietic growth factors. 271 8


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