Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunomodulatory drugs (IMiDs) are potent inhibitors of TNF-alpha and IL-1beta and elevators of IL-10 production in LPS-stimulated human PBMC. They are currently in clinical trials for various diseases, including multiple myeloma, myelodysplastic syndrome, and melanoma. In the present study, we have investigated the effects of thalidomide, CC-5013 and CC-4047 on the expression of COX-2 by stimulated PBMC. Our results show that thalidomide and IMiDs inhibited the expression of COX-2 but not the COX-1 protein in LPS-TNF-alpha and IL-1beta stimulated PBMC and shortened the half-life of COX-2 mRNA in a dose-dependent manner. They also inhibited the synthesis of prostaglandin E2 from LPS-stimulated PBMC. While anti-TNF-alpha or IL-1beta neutralizing antibodies had no effect on COX-2 expression, anti-IL-10 neutralizing antibody elevated the expression of COX-2 mRNA, and protein from treated PBMC. These data suggest that the anti-inflammatory and anti-tumor effects of IMiDs may be due in part to elevation of IL-10 production and its subsequent inhibition of COX-2 expression.
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PMID:Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. 1559 23

The myelodysplastic syndromes (MDS) can be divided into "early" and "advanced" disease by evaluation of prognostic variables such as the number of cytopenias, karyotype, and percentage of myeloblasts. Patients with an isolated interstitial deletion of chromosome 5q31 represent a distinct subset who may derive particular benefit from immunomodulatory drugs. Goals of therapy for early MDS focus on hematologic improvement and maximizing quality of life. Thalidomide, the prototype of the immunomodulatory drugs, yields major erythroid responses in some patients with early MDS, but dose-limiting neurologic toxicities limit its potential clinical benefit. Lenalidomide, a more potent and non-neurotoxic derivative, has shown promising results in early MDS, yielding hematologic improvement in almost half of patients, and transfusion independence with cytogenetic remissions in approximately two thirds of patients harboring the chromosome 5q31 deletion.
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PMID:Lenalidomide (Revlimid, CC-5013) in myelodysplastic syndromes: is it any good? 1586 69

Myelodysplastic syndromes (MDS) encompass a spectrum of clinically diverse hematopoietic stem cell malignancies for which there are few treatment options. These disorders display remarkable heterogeneity in their hematologic and pathologic features, with a wide-ranging natural history. Complex interactions between the affected clone and the bone marrow microenvironment drive the pathogenesis and progression of MDS, resulting in ineffective hematopoiesis, blast accumulation, and a variable predisposition for progression to acute leukemia. For early stage, lower-risk patients with MDS, the mainstay of therapy is supportive care, especially red blood cell transfusions, to alleviate the symptoms of anemia. However, these interventions do not target the underlying pathobiology of disease and have questionable impact on the natural disease course. Dysregulated inflammatory, apoptotic, and angiogenic cytokines play major roles in the pathobiology of MDS and represent attractive therapeutic targets. Lenalidomide is an orally bioavailable analogue of thalidomide with more potent immunomodulatory, antiangiogenic, and antitumor activities than the parent compound and with a better safety profile. In nonclinical studies, the effects of lenalidomide include potentiation of clonogenic response to erythropoietin, activation of integrin-mediated adhesion, cell cycle arrest, sensitization to apoptotic signals, and abrogation of cellular response to receptor-initiated trophic signals. These effects have the potential to impact survival and apoptosis of erythropoietic progenitor cells and their progeny. Data from clinical trials of lenalidomide in MDS have shown erythropoietic- and cytogenetic-remitting activities that frequently result in transfusion independence, particularly in patients with 5q- deletion and lower-risk MDS. Decreases in microvessel density in bone marrow specimens from responding patients provide supportive evidence of an antiangiogenic effect in MDS. Adverse effects, most commonly myelosuppression, are generally manageable with dose reduction and growth factor support. Multicenter phase II and III studies are under way to further assess the erythroid and cytogenetic response rates in distinct subtypes of MDS, including 5q- deletion, and to optimize its clinical application.
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PMID:Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS). 1608 15

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.
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PMID:Properties of thalidomide and its analogues: implications for anticancer therapy. 1614 35

After nearly decades of extinction as a sedative and antiemetic, thalidomide reemerged as the parent compound of a novel and promising class of therapeutics termed the immunomodulatory drugs (IMiDs). The analogues of thalidomide, CC-5013 (lenalidomide, Revlimid) and CC-4047 (Actimid) are more potent regulators of cellular immune and cytokine response while lacking some of the dose limiting side effects of the parent compound, such as neurologic toxicity. Preclinical data will be reviewed that outlines these drugs' effects on tumor necrosis alpha, interleukin 12, angiogenesis, and T-cell function. The evolution of the use of thalidomide as a therapeutic for diseases such as multiple myeloma and myelodysplastic syndrome and the promising initial results of the new IMiDs will be reviewed.
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PMID:Immunomodulatory drugs. 1630 90

Thalidomide has demonstrated a broad spectrum of pharmacological and immunological effects, with potential therapeutic applications that span a wide spectrum of diseases: cancer and related conditions; infectious diseases; autoimmune diseases; dermatological diseases; and other disorders such as sarcoidosis, macular degeneration and diabetic retinopathy. Immunomodulatory derivative lenalidomide has more potent antitumour and anti-inflammatory effects. The molecular mechanisms of antitumour activity of lenalidomide have been extensively studied in multiple myeloma (MM). It directly induces growth arrest and/or apoptosis of even drug-resistant MM cells; inhibits binding of MM cells to bone marrow extracellular matrix proteins and stromal cells; modulates cytokine secretion and inhibits angiogenesis in the bone marrow milieu; and augments host antitumour immunity. Importantly, lenalidomide induces significant clinical responses even in patients with relapsed/refractory MM. Therefore, lenalidomide represents a new class of antitumour agents that is useful in the treatment of MM. Lenalidomide has received fast track designation from the FDA for the treatment of MM and myelodysplastic syndromes.
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PMID:Current therapeutic uses of lenalidomide in multiple myeloma. 1643 96

Lenalidomide (Revlimid, CC-5013) belongs to a line of compounds known as immunomodulatory drugs (IMiDs) that are under clinical investigation in hematopoietic and solid tumor cancers. Lenalidomide efficacy has been reported in clinical trials of multiple myeloma and myelodysplastic syndromes (MDS), particularly in MDS patients with a del 5q cytogenetic abnormality, with or without other cytogenetic abnormalities. Here we report that lenalidomide inhibits proliferation of chromosome 5 deleted hematopoietic tumor cell lines in vitro, whether from the B cell, T cell, or myeloid lineage. There was diversity in the responses of the various cell lines to lenalidomide, with one undergoing cell cycle arrest, and others undergoing apoptosis. In the most lenalidomide-sensitive chromosome 5 deleted cell line, Namalwa CSN.70, the compound induced G0/G1 cell cycle arrest, inhibited Akt and Gab1 phosphorylation, and inhibited the ability of Gab1 to associate with a receptor tyrosine kinase. Lenalidomide also enhanced AP-1 transcriptional activity in Namalwa, but not in the other cell lines tested. These studies provide evidence for the mechanism of action of lenalidomide in chromosome 5 deleted hematopoietic tumors in vitro, and may provide a better understanding of the drug's activity in clinical applications.
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PMID:Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly. 1649 42

Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells characterized by ineffective hematopoiesis. The result is pancytopenia leading to transfusion-dependent anemia, an increased risk of infection or bleeding, and a potential to progress to acute myeloid leukemia (AML). MDS is most prevalent among older individuals, many of whom also suffer from other medical conditions. MDS is classified according to World Health Organization criteria and the International Prognostic Scoring System. Supportive care remains the mainstay of therapy. Those with low-risk MDS can often be monitored for an extended period of time without specific therapy, whereas those with intermediate- or high-risk MDS benefit from treatment. Currently, only azacitidine is approved for the treatment of MDS. Several new agents are being tested, including inhibitors of angiogenesis (thalidomide, lenalidomide), farnesyl transferase inhibitors (lonafarnib, tipifarnib), and DNA methyltransferase inhibitors (azacitidine, decitabine). Lenalidomide appears particularly effective in patients with low-risk MDS with the deletion of chromosome 5q31. Allogeneic stem cell transplantation is an alternative for high-risk MDS. With advances in transplantation techniques, this treatment can be offered to an increasing number of patients. However, it is necessary to assess each patient's disease individually and to evaluate prognostic factors, other treatment options, and the appropriateness and timing of transplantation.
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PMID:Myelodysplasia: when to treat and how. 1651 26

Lenalidomide (CC-5013; Revlimid) represents one compound in a category of new medications known as immunomodulatory drugs. These compounds are thalidomide derivatives. Through relatively minor structural modifications, the potency of the medication is improved compared with the parent compound, and the side-effect profile has changed considerably. The neurologic toxicity and pro-thrombotic effects of thalidomide are reduced in the structural analog, although concerns regarding pro-thrombotic effects are still present when lenalidomide is combined with dexamethasone. Data supporting lenalidomide's use in myelodysplastic syndrome and multiple myeloma has been published over the past several years and presented at the May 2005 meeting of the American Society of Clinical Oncology. Further trials are ongoing for many other malignancies. This report will review the preclinical and clinical results of the investigations with this exciting new therapeutic, its toxicities and future prospects.
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PMID:Lenalidomide: an immunomodulatory drug. 1655 34

Deletions of the long (q) arm of chromosome 5 [del(5q)]occur in patients with myelodysplastic syndromes (MDS) including, but not limited to, those who meet the WHO definition of the 5q- syndrome. Del(5q) MDS patients frequently have symptomatic anemia, and its treatment has traditionally consisted of RBC transfusions and, for some, iron chelation therapy. Erythropoietin, darbepoetin, hypomethylating agents, and lenalidomide can enhance erythropoiesis in MDS patients with anemia, increasing hemoglobin levels and abrogating RBC transfusion requirements. Lenalidomide is particularly active in treating the anemia of del(5q) MDS, which is especially relevant given the low response rate to erythropoietin in this group of patients. In a recent study of 43 MDS patients, 10 of 12 patients (83%) with del(5q) MDS achieved sustained RBC transfusion independence (or a > 2 g/dL increase in hemoglobin), compared with 57% of those with a normal karyotype and 12% of those with other karyotypic abnormalities. Complete cytogenetic remissions were achieved in 75% (nine of 12) of the del(5q) MDS patients, suggesting that lenalidomide targets a fundamental pathogenetic feature of MDS that is more pronounced in the presence of chromosomal 5q deletions. This review highlights some issues about the classification and treatment of del(5q) MDS.
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PMID:Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. 1673 11


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