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)

Chronic myelogenous leukemia (CML) is a progressive and often fatal hematopoietic neoplasm characterized by the presence of the Philadelphia chromosome. This arises from a balanced translocation between chromosomes 9 and 22, creating the bcr-abl fusion gene. It is often stated that the only proven curative option is allogeneic stem cell transplantation, which is indicated for only a limited subset of patients. The Bcr-Abl tyrosine kinase inhibitor imatinib represented a major advance over conventional CML therapy. After imatinib treatment, > 90% of patients had a complete hematologic response, and 70%-80% had a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging and exhibit a major change in the natural history of the disease. The understanding of some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that might overcome this resistance. The outlook today for patients with CML is much brighter than that of a few years ago.
Clin Lymphoma Myeloma 2007 Mar
PMID:Management of patients with newly diagnosed chronic myeloid leukemia: opportunities and challenges. 1738 13

The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). Complete cytogenetic remissions are standard for patients treated in chronic phase; however, treatment outcomes in advanced-phase disease are far less promising. Because hematopoietic cell transplantation is potentially curative in CML and newer TKIs are now available, the use of imatinib necessitates careful monitoring in order to identify cases in which transplantation or alternative TKI therapy might be indicated. Monitoring CML with cytogenetics and molecular methods such as the polymerase chain reaction can define subsets of patients at low or high risk of relapse and progression. In this review, we define the types of tests used to monitor the disease, provide clinically relevant endpoints, and outline guidelines for monitoring patients with CML receiving imatinib therapy.
Clin Lymphoma Myeloma 2007 Mar
PMID:Monitoring patients with chronic myeloid leukemia receiving Abl tyrosine kinase inhibitor therapy. 1738 14

Chronic myelogenous leukemia is one of the leukemic disorders more responsive to immunotherapy. Interferon-based regimens were the first treatment to produce complete cytogenetic responses, and this agent has been classified as an immunotherapeutic agent. Although most patients are now treated with imatinib as first-line therapy, a combination of interferon and imatinib could increase the rate of molecular responses and prevent patients from experiencing relapse. Thus, large phase III trials are currently exploring this strategy. Allogeneic stem cell transplantation also involves the immune system, with fewer patients in relapse in case they experience graft-versushost disease. Vaccine strategies are also promising with phase II ongoing trials. These vaccine strategies include the use of oligopeptides derived from the Bcr-Abl junction. Initial results indicate a good safety profile of these therapies in patients exhibiting complete cytogenetic response and molecular responses. These 3 different approaches of immunotherapy are described herein. Although these results obtained with imatinib are promising, this tyrosine kinase inhibitor does not eradicate leukemic stem cells. Thus, immunotherapeutic strategies are still being investigated in chronic myelogenous leukemia.
Clin Lymphoma Myeloma 2007 Mar
PMID:Immunotherapy in chronic myelogenous leukemia. 1738 15

The lessons learned from the remarkably successful use of the first-generation tyrosine kinase inhibitor (TKI) imatinib in patients with chronic myeloid leukemia resulted in a major paradigm shift in the treatment of many human cancers, and now further lessons are being learned from our enhanced understanding of the molecular mechanisms of resistance to imatinib and second-generation TKIs, particularly dasatinib and nilotinib. Although diverse mechanisms seem to be involved, the principal cause appears to be the emergence of point mutations in the Abl kinase domain that affect drug affinity and some of which impair the efficacy with which the drugs bind. Currently, > 50 different mutations have been identified, and the extent to which they confer resistance varies considerably. One of the more common mutations results from the substitution of isoleucine for threonine at Abl amino acid position 351, known as the T315I mutation. It appears that the precise position of the substitution within the kinase domain dictates the degree of resistance to TKIs, and patients with the T315I mutation develop almost complete resistance to imatinib, dasatinib, and nilotinib. Herein, we discuss the emerging strategies for circumventing resistance associated with the Bcr-Abl T315I mutation.
Clin Lymphoma Myeloma 2007 Mar
PMID:Emerging strategies for the treatment of mutant Bcr-Abl T315I myeloid leukemia. 1738 17

Allogeneic hematopoietic stem cell transplantation with an human leukocyte antigen-matched related or unrelated donor has been the curative treatment of choice for young patients with chronic phase chronic myelogenous leukemia. The introduction of imatinib, a selective inhibitor of the Bcr-Abl protein kinase, as well as a new generation of other tyrosine kinase inhibitors that are effective in obtaining major and complete cytogenetic responses with minimal toxicity, has resulted in significant changes in the standard approach for newly diagnosed patients. In this article, we will address the role of allogeneic transplantation in the context of imatinib and other tyrosine kinase inhibitors.
Clin Lymphoma Myeloma 2007 Mar
PMID:Allogeneic hematopoietic progenitor cell transplantation for the treatment of chronic myelogenous leukemia in the era of tyrosine kinase inhibitors: lessons learned to date. 1738 18

Imatinib and other Abl tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib, have significantly improved the outcome of patients with chronic myeloid leukemia. Imatinib and dasatinib are currently Food and Drug Administration (FDA) approved, and nilotinib is expected to gain FDA approval soon. In addition, several other Abl TKIs are being evaluated in various clinical trials. Imatinib has also shown efficacy in the therapy of gastrointestinal stromal tumors, Philadelphia chromosome-positive acute lymphocytic leukemia and hypereosinophilic syndrome. Because of their efficacy, more patients will receive Abl TKIs for a longer period of time. Imatinib was FDA approved after a short follow-up because of its exceptional efficacy and safety profile. The most common adverse events reported included fluid retention, fatigue, diarrhea, and muscle cramps. With longer follow-up, issues related to the long-term use of imatinib have been discussed. Our aim is to review the emerging safety issues of Abl TKIs after a longer follow-up.
Clin Lymphoma Myeloma 2007 Mar
PMID:Emerging safety issues with imatinib and other Abl tyrosine kinase inhibitors. 1738 19

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, which is associated with a balanced translocation involving chromosomes 9 and 22 to produce a fusion gene (bcr-abl) that gives rise to a constitutively activated Abl tyrosine kinase. This kinase led to the discovery of several small-molecule inhibitors, imatinib being the first and most successful of these. Resistance to imatinib results in some patients from Abl kinase point mutations. Overcoming imatinib resistance represents one of the biggest challenges facing clinicians in the modern management of CML. In this review, we discuss the current understanding of CML pathophysiology and mechanisms of imatinib resistance and how advancing this knowledge has led to the design of novel therapies in the area of blastic phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia with previous imatinib failure.
Clin Lymphoma Myeloma 2007 Mar
PMID:Novel Abl kinase inhibitors in chronic myeloid leukemia in blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia. 1738 20

In 2006, most newly diagnosed patients with chronic myeloid leukemia (CML) underwent first-line, molecular-targeted therapy with the Bcr-Abl tyrosine kinase inhibitor, imatinib. The expectation was that the vast majority of these patients would exhibit a complete cytogenetic response on imatinib alone. Studies of patients with acquired imatinib resistance revealed that Bcr-Abl signaling is reactivated at the time of resistance, predominantly because of mutations that interfere with drug binding in the kinase domain of Bcr-Abl. The knowledge that Bcr-Abl remains the optimal target for treating imatinib-refractory CML has driven an already highly successful search for alternative approaches to restore target inhibition. Here, we review the current state of affairs in the realm of controlling drug resistance in CML, including cutting-edge strategies to reign in Bcr-AblT315I, which is cross resistant to imatinib, as well as the "next generation" Bcr-Abl inhibitors, nilotinib and dasatinib. We also critically assess the role of combined Abl kinase inhibitor therapy in overcoming resistance and provide recommendations for monitoring patients for kinase domain mutations.
Clin Lymphoma Myeloma 2007 Mar
PMID:Bcr-Abl kinase domain mutations and the unsettled problem of Bcr-AblT315I: looking into the future of controlling drug resistance in chronic myeloid leukemia. 1738 21

Chronic myeloid leukemia cells contain a Bcr-Abl oncoprotein with an enhanced tyrosine kinase activity, which is considered to be the principal cause of the leukemia. The use of the first-generation tyrosine kinase inhibitor imatinib to inhibit the dysregulated kinase activity has proved remarkably successful, and imatinib as a single-agent is now considered to be the best initial treatment for the majority of adult patients in chronic phase. For patients who develop resistance to imatinib, the Bcr-Abl signaling pathway is often re-activated, second generation tyrosine kinase inhibitors, such as dasatinib or nilotinib, might restore the kinase inhibition. Allogeneic stem cell transplantation is now generally offered to older patients in whom imatinib therapy, and perhaps dasatinib or nilotinib also, have failed; efforts to establish firm criteria for the selection of second-line therapies after imatinib failure continue. At this time, children and younger adults should probably be considered for transplantation as first-line treatment.
Clin Lymphoma Myeloma 2007 Mar
PMID:Optimal management of patients with newly diagnosed chronic phase chronic myeloid leukemia in 2007. 1738 23

VEGF (vascular endothelial growth factor), a potent angiogenic molecule specific for vascular endothelial cells, is overexpressed in most tumours including MM (multiple myeloma) and closely associated with tumour growth and prognosis. It has been shown that a soluble fragment of the VEGF receptor Flt-1 (Fms-like tyrosine kinase-1) [sFlt-1 (soluble Flt-1)] has antiangiogenic properties by way of its antagonist activity against VEGF. VEGF and its receptors have been shown to be targets for treating tumours. In the present study, sFlt-1 gene was expressed in Pichia pastoris and the product was applied for studying the effect on KM3 MM cells. sFlt-1 gene was inserted into the pPICZalphaA vector and the expressed product was analysed by SDS/PAGE, immunoblot and ELISA. The sFlt-1 protein was expressed by 0.5% (v/v) methanol induction and it accumulated up to 23% of total proteins in the supernatant. The product was further purified with metal-chelating resin [Ni-NTA (Ni(2+)-nitrilotriacetate)]. The functional analysis of the sFlt-1 protein was performed with HUVEC (human umbilical-vein endothelial cells) proliferation assay. We next showed that the sFlt-1 protein acted directly on MM cells and inhibited the VEGF-induced proliferation of MM cells with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] and (3)H uptake assay. The sFlt-1 protein blocked VEGF-induced ERK (extracellular-signal-regulated kinase) phosphorylation and inhibited the MAPK (mitogen-activated protein kinase) signalling cascades. The present study demonstrated that anti-MM activity of the sFlt-1 protein, coupled with its antiangiogenic effects, provides the basis for clinical trials of this agent to improve the outcome in MM.
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PMID:Expression of soluble Flt-1 gene in Pichia pastoris and the effect of the product on multiple-myeloma cells in vitro. 1761 89


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