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)

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.
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PMID:Thalidomide for erythema nodosum leprosum and other applications. 1268 Apr 78

Thalidomide the first commercially available immune modulatory drug (IMiD), has activity in the treatment of Waldenstrom's macroglobulinemia (WM), as well as multiple myeloma, myelodysplastic syndrome, myelofibrosis with myeloid metaplasia, chronic lymphocytic leukemia (CLL), and B-cell lymphomas. Although its molecular mechanisms of action have not yet been elucidated, thalidomide and the IMiDs affect a variety of cytokines and inflammatory mediators including tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, interferon gamma (IFNgamma), IL-6, IL-10, IL-12, and COX-2 and angiogenesis factors such as vascular endothelial growth factor (VEGF) and its receptor. The IMiDs also affect adhesion molecules such as ICAM-1, ICAM-2, and L-CAM, in addition to preferentially stimulating CD8 cells and expanding natural killer (NK) cell populations. Since most IMiDs share these properties, it would be expected that the second-generation IMiDs (REVIMID, ACTIMID) would have activity similar to thalidomide in WM with an improved safety profile. TNFalpha and angiogenesis most likely play a role in promoting the growth and development of WM. The selective cytokine inhibitory drugs (SelCIDs) are potent phosphodiesterase 4 (PDE-4) inhibitors that inhibit TNFalpha production and are highly antiangiogenic. In addition, inhibition of PDE-4 induces apoptosis in human CLL lymphocytes. It is therefore expected that the SelCIDs might have activity in Waldenstrom's tumors. Jun N-terminal kinase (JNK) is a component of signaling cascades that modulate apoptosis, the induction of an inflammatory response via the AP-1 pathway, and modulation of cellular proliferation. In a variety of tumors, including multiple myeloma, JNK is induced as part of a protective mechanism. It is hypothesized that inhibition of JNK activity might allow other chemotherapeutic agents to be more effective in a similar manner to corticosteroids. Work is in progress to evaluate this. Inhibitors of the E3 subunit of ubiquitin ligase may also selectively modulate the expression of receptors, growth factors, and transcription factors essential to the growth, survival, and spread of tumors. We hypothesize that the IMiDs, SelCIDs, JNK inhibitors, and ligase inhibitors will be the basis for a new nonchemotherapeutic approach to the treatment of WM and other related diseases.
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PMID:Potential new therapeutics for Waldenstrom's macroglobulinemia. 1272 Jan 52

Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.
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PMID:Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide. 1273 Sep 64

Anemia of variable severity occurs in more than two-thirds of patients with multiple myeloma (MM). Besides the altered cytokine network, chronic erythropoietn deficiency, blood loss and hemolysis, we have shown that deregulated myeloma cell apoptosis contributes to progressive destruction of the erythroid matrix by inducing erythroblast cytotoxicity. To exert this effect, highly malignant plasma cells overexpress both Fas-L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which efficiently trigger the death of immature erythroblasts. However, this Fas-L/TRAIL-based anemia occurs in particular in patients with severely progressive MM, thus suggesting that these apoptogen receptors may characterize a peculiar cytotoxic-apoptogenic phenotype of malignancy. Immunophenotyping of myeloma cells could help to identify patients with a higher risk of erythropoiesis exhaustion.
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PMID:Upregulation of erythroblast apoptosis by malignant plasma cells: a new pathogenetic mechanism of anemia in multiple myeloma. 1273 14

Anemia is a prominent feature of multiple myeloma (MM) and is commonly associated with clinical progression of MM. In addition to being affected by a number of pathogenetic events, including imbalance of the cytokine network, inappropriate erythropoietin (EPO) levels, blood loss, and hemolysis, the erythroid matrix is chronically deteriorated by the malignant plasma cell clone that activates a cytotoxic mechanism directed at the erythroid progenitors. In particular, malignant plasma cells express very high levels of apoptogenic receptors, including both Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand, which trigger apoptosis of immature erythroblasts by stimulating specific death receptors, namely Fas and the complex DR4/DR5. Erythroid cells also weakly express the transcription factor GATA-1, which drives erythroblast maturation by inhibiting apoptosis through antiapoptotic molecules such as EPO and Bcl-xL. This newly discovered pathogenetic mechanism of anemia in MM is based on persistent erythroblast cytotoxicity within the bone marrow that leads to progressive destruction of the erythroid matrix.
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PMID:Recent advances in understanding the pathogenesis of anemia in multiple myeloma. 1295 5

Multiple myeloma (MM) is an incurable B-cell malignancy able to mediate massive destruction of the axial skeleton. The aim of this study was to examine the involvement of the tumor necrosis factor-ligand family member, receptor activator of nuclear factor-kappaB ligand (RANKL), and its naturally occurring antagonist, osteoprotegerin (OPG), in MM biology. Using flow cytometry and two independent anti-RANKL antibodies, we demonstrate RANKL expression in CD38(+++)CD45(+) and CD38(+++)CD45(-) myeloma plasma cell (MPC) subpopulations derived from patients with osteolytic MM. In addition, highly purified subpopulations of MPC express mRNA for both transmembrane and soluble RANKL isoforms but lack expression of OPG mRNA and protein. We also show that RANKL expressed by MPC is functional as in vitro coculture of CD38(+++)CD45(+) and CD38(+++)CD45(-) MPC subpopulations with peripheral blood mononuclear cells resulted in the formation of multinucleate, tartrate-resistant acid phosphatase-positive osteoclasts-like cells capable of forming typical resorption pits. Furthermore, high expression of membrane-associated RANKL by CD38(+++) MPC correlated with the presence of multiple radiological bone lesions in individuals with MM. Together, our data strongly suggest that RANKL expression by MPC confers on them the ability to participate directly in the formation of osteoclast in vivo and extends our knowledge of the involvement of RANKL and OPG in the osteolysis characteristic of this disease.
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PMID:Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. 1474 98

Multiple myeloma (MM) is a progressive disease that is thought to result from multiple genetic insults to the precursor plasma cell that ultimately affords the tumor cell with proliferative potential despite its differentiated phenotype and resistance to undergoing apoptosis. Altered expression of antiapoptotic factors as well as growth factors have been described in a significant number of patients. However, the key regulatory elements that control myeloma development and progression remain largely undefined. Because of the knowledge that B-lymphocyte stimulator (BLyS), a tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis, promotes the survival of malignant B cells, we began a coordinated study of BLyS and its receptors in MM. All MM cells studied expressed one or more of 3 known receptors (B-cell maturation antigen [BCMA], transmembrane activator and CAML interactor [TACI], and B-cell activating factor receptor [BAFF-R]) for BLyS; however, the pattern of expression was variable. Additionally, we provide evidence that BLyS can modulate the proliferative capacity and survival of MM cells. Finally, we provide evidence that BLyS is expressed by MM cells and is present in the bone marrow of patients with MM. Expression of BCMA, TACI, and BAFF-R by MM taken together with the ability of BLyS to support MM cell growth and survival has exciting implications because they may be potential therapeutic targets.
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PMID:Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. 1451 99

Multiple myeloma (MM) is commonly associated with anemia. Several causes have been implicated, but anemia of chronic disease with inadequate erythropoietin (EPO) production related to the inflammatory cytokines appears to be of utmost importance. Interleukin-1 and tumor necrosis factor are capable of suppressing erythropoiesis. Anemia has broad implications. First, the low hemoglobin and hematocrit are associated with poor quality of life and performance and affect daily activity. Second, anemia has an impact on the cardiovascular system. Considering that most MM patients are elderly, this may be even more important. Anemia has been shown to induce or aggravate hypoxia and ischemic complications. Third, anemia has been shown to be a poor prognostic factor in MM. Traditionally, patients with symptomatic anemia were treated with red blood cell transfusions as needed. The introduction of epoetin alfa and epoetin beta into clinical practice opened new avenues to these patients. The administration of epoetins to patients with MM and anemia have been shown to be very useful. Several studies in more than 1000 patients have demonstrated a high response rate (range, 25%-85%; mean, 60%). This response is characterized by a significant increase of hemoglobin, hematocrit, and the number of red blood cells together with a reduction in the blood transfusion requirements. This is also associated with an improved quality of life. Although there is no complete agreement about the role of pretreatment serum EPO levels, many investigators believe that relatively low levels may help in predicting response, thereby limiting the number of potential candidates to receive this expensive therapy. The epoetins are safe and well tolerated with minimal toxicity; however, some concern has been recently raised regarding several dozen patients who developed pure red cell aplasia while on epoetin therapy. However, this adverse effect appears to be extremely rare. Recent data suggest that EPO has additional biologic effects, such as longer-than-expected survival in patients with MM. This observation is further supported by animal studies, demonstrating an antimyeloma effect of EPO in mice models. This effect has been shown to be immune mediated. If these exciting data are confirmed in future clinical trials, this may have significant implications on the treatment of MM.
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PMID:The implications of anemia in multiple myeloma. 1455 75

The CD14+CD16+ monocytes appear to be important to immune defense against infection, as these cells are very potent with respect to tumor necrosis factor (TNF) production, phagocytosis, and antigen presentation. Myeloablative high-dose chemotherapy (HDT) and subsequent autologous stem-cell transplantation (ASCT) are being used increasingly for therapy of hematological malignancies, but the pronounced immunosuppression renders the patients prone to infection. To determine the functional properties of CD14+CD16+ monocytes under these conditions, 15 patients with lymphoma or myeloma were examined. Before HDT, the ratio of CD14+CD16+ cells to the population of the classical CD14++ monocytes was 0.28 +/- 0.12; this ratio changed during the course of HDT and ASCT in favor of the CD14+CD16+ monocytes to a maximum of 12.4 +/- 7.8 (P<0.001) on day 3.5 +/- 1.6 after transplanation (Tx) and returned to 0.11 +/- 0.07 (P<0.001) after engraftment on day 11.3 +/- 2.2. Although the absolute number of classical CD14++ monocytes declined to less than 1/microl at the nadir, the number of CD14+CD16+monocytes fell from 29.7 +/- 9.8/microl to 4.5 +/- 3.0/microl at the nadir and increased to 13.8 +/- 9.8/microl at the day of discharge from the hospital. Flow cytometric analysis of phagocytosis of fluorescein isothiocyanate (FITC)-labeled Escherichia coli showed that 30 +/- 10% CD14+CD16+ monocytes of patients were FITC-positive before Tx, and at engrafment, the percentage of FITC-positive cells had doubled to 60 +/- 6% (healthy controls, 41+/-7%). When determining generation of reactive oxygen species after E. coli ingestion, the CD14+CD16+ monocytes showed a decreased response before Tx (32+/-12% positve cells), which increased to 53 +/- 24% after ASCT. The median fluorescence intensity of human leukocyte antigen (HLA)-DR expression on the CD14+CD16+ monocytes increased from 11 +/- 6 before Tx to 17 +/- 11 after Tx, and the production of TNF after lipopolysaccharide showed no remarkable difference (46+/-13 vs. 49+/-14 channels). At the same time, expression of TNF and of HLA-DR showed a dramatic decrease in the CD14++ monocytes. Taken together after stem-cell Tx, the function of the CD14++ monocytes is impaired, and the functional properties of CD14+CD16+ monocytes recover, indicating that these cells may be important for defense against infections post-ASCT.
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PMID:Autologous stem-cell transplantation restores the functional properties of CD14+CD16+ monocytes in patients with myeloma and lymphoma. 1457 64

Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and multiple myeloma and effectively reduces tumor necrosis factor-alpha (TNF-alpha) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-alpha and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-alpha inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-alpha secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-alpha secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-alpha mRNA stability via its 3'-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-alpha inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-alpha inhibitory activity.
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PMID:Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. 1461 24


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