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)

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

A 72-year-old male had complained of right back pain and bleeding from his tongue. He was admitted to our department on May 18, 1989. Physical examination revealed hepatosplenomegaly. Peripheral blood findings were as follows: RBC was 3.80 x 10(6)/microliters. Hb 12.2 g/dl, Ht 36.5%, platelet count 735 x 10(3)/microliters, WBC 22,100/microliters, leukoerythroblastosis present. Neutrophil alkaline phosphatase score was normal. Serum vitamin B12 and plasma platelet-derived growth factor level were elevated. Skeletal X-ray revealed multiple punched-out lesions at the 8th thoracic vertebra, and 6th and 8th ribs. Serum IgG level was 3,900 mg/dl. Serum immunoelectrophoresis revealed IgG lambda-type M-protein. Because he complained of severe cervical pain, and skeletal X-ray examination revealed the fracture of 6th cervical vertebra, the operation was performed to remove the lesion. Biopsy of cervical lesion revealed plasmacytoma. M-protein was decreased and the size of the tumor was reduced after treatment with VCAP (vincristine, cyclophosphamide, adriamycin, prednisolone) regimen and interferon-alpha for multiple myeloma.
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PMID:[IgG lambda-type multiple myeloma associated with myelofibrosis accompanied by thrombocytosis]. 194 35

The presence of active transforming growth factor-beta (TGF-beta) in serum has not been widely accepted. In particular, although at least five studies have concluded that active TGF-beta is present in normal human plasma and serum, assays that use the extracellular domain of the TGF-beta type II receptor as a capture agent have given contradictory results. We show that there is an antagonist present in normal human serum which inhibits the binding of active TGF-beta to the extracellular domain of the TGF-beta type II receptor when it is coated on the well of an ELISA plate. This antagonist activity is due to a pool of immunoglobulins of the G2, D and M classes. Moreover, we show that this same pool of immunoglobulins also recognizes the extracellular domain of the platelet-derived growth factor alpha-receptor, insulin-like growth factor-1 receptor and interleukin-3 receptor, by serial transfer of serum over the different receptors. In addition, the same immunoglobulin pool inhibits the binding of platelet-derived growth factor-AA to its receptor, in an analogous way to the inhibition of binding of TGF-beta to its type II receptor. Circumstantial evidence suggests that the pool of immunoglobulins is recognizing a carbohydrate residue that is attached to the protein when it is synthesized by the mouse myeloma cell line, NSO, in which it is made. If the cytokine receptors are similarly glycosylated in vivo, then the presence of these antibodies in normal human serum may modulate physiological cytokine signalling.
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PMID:An antibody present in normal human serum inhibits the binding of cytokines to their receptors in an in vitro system. 1049 20

Glomerulopathic monoclonal light chains (G-LC) interact with mesangial cells (MC), resulting in alterations of mesangial homeostasis. Early signaling events control mitogenic activities and cytokine production, which in turn participate in the subsequent pathologic events. Mesangial homeostasis is affected in two very different ways, depending on whether the G-LC is from a patient with light chain deposition disease (LCDD) or light chain-related amyloidosis (AL-Am). In contrast, tubulopathic (T)-LC chains from patients with myeloma cast nephropathy do not significantly interact with MC and result in no alterations in mesangial homeostasis. Therefore, understanding early events in the monoclonal LC-MC interactions is fundamental. MC in culture were exposed to LC obtained and purified from the urine of patients with plasma cell dyscrasias and biopsy-proven renal disease, including LCDD, AL-Am, and myeloma cast nephropathy. Incubation of MC with G-LC, but not T-LC, resulted in cytoskeletal and cell shape changes, activation of platelet-derived growth factor-beta (PDGF-beta) and its corresponding receptor, cytoplasmic to nuclear migration of c-fos and NF-kappa beta signals, and production of monocyte chemoattractant protein-1 (MCP-1), as well as increased expression of Ki-67, a proliferation marker. Although NF-kappa beta activation was directly related to MCP-1 production, c-fos activation regulated proliferative signals and cytoskeletal changes in MC. Amyloidogenic LC were avidly internalized by the MC, whereas LCDD-LC effector targets were located at the MC surface. These cellular events are likely initiated as a result of interactions of the G-LC with yet-uncharacterized MC surface receptors. Dissecting the events taking place when G-LC interact with MC may define potential important targets for selective therapeutic manipulation to ameliorate or prevent the glomerular injury that ensues.
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PMID:Monoclonal light chain--mesangial cell interactions: early signaling events and subsequent pathologic effects. 1135 Oct 41

Osteoclasts and osteoblasts are responsible for strict bone maintenance with a balance between bone formation and resorption by interacting with each other. Recently, it has been revealed that osteoblasts/stromal cells regulate differentiation of osteoclasts/hematopoietic cells by two factors, the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) on the plasma membrane, and secreted osteoprotegerin (OPG). However, no factors have yet been reported by which osteoclasts/hematopoietic cells regulate osteoblasts/stromal cells. To elucidate the possibility of signal transduction from osteoclasts to osteoblasts, we studied the conditioned medium of mouse osteoclast-like myeloma cell line RAW264.7 treated with RANKL. We found that this medium contains a factor that inhibits differentiation of mouse osteoblast precursor-like cell line MC3T3-E1 to osteoblasts induced by bone morphogenetic protein 4 (BMP-4) and named this factor osteoblastogenesis inhibitory factor (OBIF). OBIF was purified by successive three-step chromatography by heparin affinity, anion exchange, and reversed-phase columns. Osteoblastogenesis inhibitory activity made one peak in each chromatography step, showing the factor is a single entity. Active fractions were loaded on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and bands of proteins were excised, digested by trypsin, and analyzed by liquid chromatography equipped with tandem mass spectrometry (LC/MS/MS). Consequently, we have identified this factor to be platelet-derived growth factor BB (PDGF BB) homodimer. Furthermore, this identification of PDGF BB as OBIF was confirmed by neutralization of the inhibitory activity of the medium with anti-PDGF antibody. These results show, for the first time, that osteoclasts regulate osteoblasts directly and suggest that PDGF BB is a key factor in bone remodeling.
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PMID:Platelet-derived growth factor BB secreted from osteoclasts acts as an osteoblastogenesis inhibitory factor. 1181 56

Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders: hematological and nonhematological. Clinical presentation of fibrosis could occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma. The pathophysiology underlying BM fibrosis remains unclear despite intensive study, with a corresponding lack of specific therapy. This review discusses new insights in the role of substance P, cytokines and fibronectin in the development of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic properties, e.g. neurotransmission and immune/hematopoietic modulation and is linked to BM fibrosis. Cytokines and growth factors, in particular those associated with fibrogenic properties, e.g. TGF-beta, IL-1 and platelet-derived growth factor, are linked to BM fibrosis. Extracellular matrix proteins are increased in patients with BM fibrosis. Fibronectin in the sera of patients with BM fibrosis is complexed to substance P. Fibronectin appears to protect substance P from degradation by endogenous peptidases. This review describes the preliminary findings on the colocalization of substance P and fibronectin in the BM of patients with fibrosis. These data are reviewed in the context of published reports with particular focus on the relevant cytokines. A more detailed understanding of intra- and intercellular mechanisms in BM fibrosis may lead to effective therapy.
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PMID:Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis. 1248 16

New brief reports this month include: Strategies for Duchenne Muscular Dystrophy: Various approaches are being explored to abate the dystrophic process including cellular therapies (transplanting stem cells or myogenic precursors into muscles), molecular approaches (delivering a functional or correcting the mutant dystrophin gene), such as MyoDys, Biostrophin(R) and antisense technology, and pharmacotherapeutics, which include calcium channel blockers, calpain inhibitors, phosphodiesterase inhibitors and monoclonal antibodies; Immunotherapy for Multiple Myeloma: Increasing numbers of antibodies and immunoconjugates with anticancer drugs are entering clinical development; Acute respiratory distress syndrome is among the most frequent reasons for intensive care. Current medications include antibiotics, diuretics, drugs to counteract low blood pressure caused by shock, anxiolytics and antiinflammatories, while there are eight potential drugs in active development; Pulmonary Hypertension: Drugs intervening at four signaling pathways (endothelin, prostacyclin, nitric oxide and platelet-derived growth factor), which are implicated in pulmonary hypertension, include readily available bosentan, sildenafil citrate and sitaxsentan sodium and investigational aviptadil and TBC-3711, among others.
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PMID:Chronicles in drug discovery. 1639 21

Angiogenesis is a process that plays an important role in the growth and progression of cancer; growing evidence suggests that neovascularization is important in hematologic malignancies. Increased angiogenic potential has been identified in multiple myeloma (MM). In this study, investigators simultaneously measured the levels of hepatocyte growth factor (HGF), platelet-derived growth factor-AB (PDGFAB), and transforming growth factor-alpha (TGF-alpha) through enzyme-linked immunosorbent assay in the bone marrow (BM) and peripheral blood (PB) of 30 patients with MM and 10 healthy controls. Differences in HGF values in BM sera were significant (P=.001) between patients and controls. In detailed analyses of HGF, PDGF-AB, and TGF-alpha, according to disease stage, a significant correlation was found between disease stage and BM HGF (P=.047), BM TGF-alpha (P=.021), and PB PDGF-AB (P=.006), respectively. When correlations between all other parameters were analyzed, significance was noted between PB TGF-alpha and lactate dehydrogenase (P=.02), PB TGF-alpha and PB HGF (P=.002), BM TGF-alpha and CD38 (P=.046), BM TGF-alpha and BM HGF (P=.000), BM TGF-alpha and BM PDGF-AB (P=.048), BM HGF and PB HGF (P=.044), and BM PDGF-AB and PB PDGF-AB (P=.000). BM HGF levels had a significant effect on overall survival, with disease severity assessed in terms of disease stage (P=.0018, log-rank test). These data show that in patients with MM, high levels of BM HGF, BM TGF-alpha, and PB PDGF-AB were associated with advanced disease stage; in addition, HGF played a significant role in disease processing and was related to disease severity. These findings have also led to the concept of a symbiotic relationship between the growth of myeloma cells and HGF, TGF-alpha, and PDGFAB in BM.
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PMID:Clinical significance of hepatocyte growth factor, platelet-derived growth factor-AB, and transforming growth factor-alpha in bone marrow and peripheral blood of patients with multiple myeloma. 1705 May 6

Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFRbeta) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFRbeta kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRbeta/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor-tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRbeta/c-Src TKs in MM, providing a framework for future clinical trials.
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PMID:Validation of PDGFRbeta and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib. 1852 94

Nodular glomerulosclerosis results from increased deposition of extracellular matrix proteins and monotypic light chains. The inability of mesangial cells to degrade abnormal levels of tenascin-C--along with the increased expression of some growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta)--is crucial to the pathogenesis of light chain deposition disease (LCDD). In order to study the molecular processes contributing to LCDD, we grew mesangial cells in three-dimensional matrices and incubated the cells with free light chains purified from the urine of patients with biopsy-proven LCDD, immunoglobulin-associated amyloid deposits, or myeloma cast nephropathy. Light chains of the latter two cohorts served as controls. Mesangial cells incubated with light chains from patients with LCDD show a significant increase in tenascin-C expression, centrally located within newly formed nodules, along with increased expression of PDGF and TGF-betas, compared to mesangial cells incubated with control light chains. There was less extracellular MMP-7 even though its intracellular expression is markedly increased compared to the control. Addition of active MMP-7 degraded this excess tenascin-C in vitro, a process that could be prevented by an exogenous MMP inhibitor. Our in vitro model recapitulates in vivo findings in patients with LCDD, thus allowing definition of the sequential pathologic processes associated with glomerulopathic light chain interactions with mesangial cells.
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PMID:An in vitro model of light chain deposition disease. 1924 79


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