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)

We recently demonstrated that caveolae, vesicular flask-shaped invaginations of the plasma membrane, represent novel therapeutic targets in multiple myeloma. In the present study, we demonstrate that vascular endothelial growth factor (VEGF) triggers Src-dependent phosphorylation of caveolin-1, which is required for p130(Cas) phosphorylation and multiple myeloma cell migration. Conversely, depletion of caveolin-1 by antisense methodology abrogates p130(Cas) phosphorylation and VEGF-triggered multiple myeloma cell migration. The proteasome inhibitor bortezomib both inhibited VEGF-triggered caveolin-1 phosphorylation and markedly decreased caveolin-1 expression. Consequently, bortezomib inhibited VEGF-induced multiple myeloma cell migration. Bortezomib also decreased VEGF secretion in the bone marrow microenvironment and inhibited VEGF-triggered tyrosine phosphorylation of caveolin-1, migration, and survival in human umbilical vascular endothelial cells. Taken together, these studies demonstrate the requirement of caveolae for VEGF-triggered multiple myeloma cell migration and identify caveolin-1 in multiple myeloma cells and human umbilical vascular endothelial cells as a molecular target of bortezomib.
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PMID:Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib. 1549 76

Cyclopentenone prostaglandins are potent inhibitors of nuclear factor-kappa B (NF-kappa B), a transcription factor with a critical role in promoting inflammation and connected with multiple aspects of oncogenesis and cancer cell survival. In the present report, we investigated the role of NF-kappa B in the antineoplastic activity of the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) in multiple myeloma (MM) and Burkitt lymphoma (BL) cells expressing constitutively active NF-kappa B. 15d-PGJ(2) was found to suppress constitutive NF-kappa B activity and potently induce apoptosis in both types of B-cell malignancies. 15d-PGJ(2)-induced apoptosis occurs through multiple caspase activation pathways involving caspase-8 and caspase-9, and is prevented by pretreatment with the pan-caspase inhibitor ZVAD (z-Val-Ala-Asp). NF-kappa B inhibition is accompanied by rapid down-regulation of NF-kappa B-dependent antiapoptotic gene products, including cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), and FLICE-inhibitory protein (cFLIP). These effects were mimicked by the proteasome inhibitor MG-132, but not by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist troglitazone, suggesting that 15d-PGJ(2)-induced apoptosis is independent of PPAR-gamma. Knockdown of the NF-kappa B p65-subunit by lentiviral-mediated shRNA interference also resulted in apoptosis induction in malignant B cells with constitutively active NF-kappa B. The results indicate that inhibition of NF-kappa B plays a major role in the proapoptotic activity of 15d-PGJ(2) in aggressive B-cell malignancies characterized by aberrant regulation of NF-kappa B.
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PMID:15-Deoxy-delta 12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-kappa B activity and down-regulation of antiapoptotic proteins. 1549 50

Multiple myeloma (MM), a malignancy of the plasma cells, accounts for an estimated 14% of all newly diagnosed hematologic malignancies. Advances in chemotherapy and stem cell transplantation have improved survival rates, but MM remains incurable. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc., Cambridge, MA), a first-in-class proteasome inhibitor, has been approved for patients with MM who have received at least two prior treatments and have demonstrated disease progression on the most recent one. During clinical trials, most side effects were manageable with standard interventions. The most common toxicities were asthenic conditions (fatigue, malaise, and weakness), gastrointestinal disturbances (nausea, vomiting, diarrhea, and constipation), thrombocytopenia, peripheral neuropathy, pyrexia, and anemia. Supportive therapies and strategies for side-effect management can prevent worsening of these symptoms, thereby avoiding dose reductions and treatment delays. Oncology nurses play a key role in ensuring the proper and safe administration of bortezomib and often are the first to identify the signs of side effects. Patient education about anticipated side effects and close monitoring of patients can lead to symptom management interventions that are essential to patient comfort and safety.
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PMID:Bortezomib, a newly approved proteasome inhibitor for the treatment of multiple myeloma: nursing implications. 1551 81

High-dose therapy with stem cell transplantation (SCT) and novel targeted therapies (thalidomide, its more potent analogues, and bortezomib) represent two approaches for overcoming resistance of multiple myeloma (MM) cells to conventional therapies. While it is now clear that dose-intensification improves the outcome in younger patients, long-term remissions are obtained in a minority of patients. Therefore, the impact of novel agents as part of front-line therapy is the objective of ongoing trials. Gene expression profiling (GEP) will help to improve the management of MM not only by identifying prognostic subgroups but also by defining molecular pathways that are associated with these subgroups and that are possible targets for future therapies. In Section I, Dr. John Shaughnessy describes recent data obtained with GEP of CD138-purified plasma cells from patients with MM. His group has already shown that overexpression of the Wnt signaling inhibitor DKK1 by MM plasma cells blocks osteoblast differentiation and contributes to the development of osteolytic bone lesions. Recent data allow identification of four subgroups of MM in which GEP is highly correlated not only with different clinical characteristics and outcome but also with different cytogenetic abnormalities. In addition, abnormal expression of only three genes (RAN, ZHX-2, CHC1L) is associated with rapid relapses. In the context of intensive therapy with tandem autotransplantations, this model appears to be more powerful than current prognostic models based on standard biologic variables and cytogenetics. Understanding why the dysregulation of these three genes is associated with a more aggressive behavior of the disease will help to define new therapeutic strategies. In Section II, Dr. Jean-Luc Harousseau presents recent results achieved with tandem autologous SCT (ASCT) and with reduced intensity conditioning (RIC) allogeneic SCT. ASCT is now considered as the standard of care in patients up to 65 years of age. The IFM (Intergroupe Francophone du Myelome) has recently shown that double ASCT is superior to single ASCT. Current results of three other randomized trials confirm that double ASCT is superior, at least in terms of event-free survival. However, patients with poor prognostic features do poorly even after tandem ASCT. Strategies to further improve the outcome of ASCT include more intensive therapies and the use of novel agents such as thalidomide and immunomodulatory analogs (IMiDs) or bortezomib. Results of allogeneic SCT remain disappointing in MM even with T cell-depleted grafts. Preliminary results of a strategy combining ASCT to reduce tumor burden and RIC allogeneic SCT are encouraging, although the follow-up is still short. However, again, patients with chromosome 13 deletions have poor results with RIC. Longer follow-up of ongoing multicentric studies will help to clarify the indications of RIC. In Section III, Dr. Paul Richardson summarizes current knowledge of novel targeted therapies in MM. A better understanding of interactions between MM cells and bone marrow stromal cells and of the signaling cascades whereby cytokines mediate proliferation, survival, drug resistance and migration of MM cells provide the rationale for testing novel agents in relapsed/refractory MM. Increased angiogenesis coupled with the known anti-angiogenesis activity of thalidomide justified its use in refractory MM. The remarkable responses initially achieved prompted a number of clinical studies in different indications and the development of more potent IMIDs. Among them CC-5013 (Revlimid) has been tested in Phase I/II studies and a randomized Phase III study has just been completed. Blockade of NF-kappa B using the proteasome inhibitor bortezomib (Velcade) may mediate anti-MM activity by inhibiting interleukin (IL)-6 production in stromal cells and other mechanisms of action have been shown in preclinical studies. Based on the promising results of the Phase II trial, a large randomized trial of bortezomib versus dexamethasone has been completed. Studies of bortezomib combined with other drugs are ongoing. Arsenic trioxide has a number of properties showing that it targets MM cells interacting with the microenvironment. Clinical studies are ongoing as well. Other agents in MM have already been or will probably be translated soon from the bench to the bedside.
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PMID:Multiple myeloma. 1556 86

The proteasome is the main extralysosomal system involved in intracellular proteolysis. A number of proteasome substrates, including cyclins, IkappaB, and p53, are critical to cell cycle progression and apoptosis. Interruption of the degradation of these substrates through proteasome inhibition is a novel and unique approach to the treatment of malignancies. First-generation proteasome inhibitors lacked usefulness because of broad specificity and irreversible binding to the proteasome. However, the later synthesis of the peptide boronic acid proteasome inhibitor bortezomib allowed for selective, reversible binding. Basic investigations have reported the antitumor activity of bortezomib in a variety of hematologic and solid tumor models and have demonstrated the ability of bortezomib to enhance chemosensitivity and overcome cellular mechanisms of drug resistance attributable, in part, to abrogation of NF-kappaB induction. In patients with relapsed, refractory multiple myeloma who had received a median of six prior regimens, treatment with bortezomib resulted in a 35% response rate (complete plus partial plus minimal response) using criteria of the European Group for Blood and Marrow Transplantation. Encouraging activity has been demonstrated with bortezomib in the first-line treatment of myeloma and in patients with mantle cell lymphoma. Investigations of its utility in the treatment of patients with solid tumors are ongoing.
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PMID:Proteasome inhibition in the treatment of cancer. 1565 70

The 26S proteasome is a large intracellular adenosine 5'-triphosphate-dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.
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PMID:Proteasome inhibition as a novel therapeutic target in human cancer. 1565 9

Proteasome inhibition is a novel, targeted approach in cancer therapy. Both natural and synthetic proteasome inhibitors selectively penetrate cancer cells, disrupting the orderly destruction of key regulatory proteins involved in tumorigenesis and metastasis. Disrupting the orderly destruction of regulatory proteins causes an imbalance of these proteins within the cell, which interferes with the systematic activation of signaling pathways required to maintain tumor cell growth and survival; therefore, cellular replication is inhibited and apoptosis ensues. Bortezomib (PS-341, Velcade), the first proteasome inhibitor evaluated in human clinical trials, has been approved by the US Food and Drug Administration for use in patients with refractory or relapsed multiple myeloma. Preclinical study results show that bortezomib suppresses tumor cell growth, induces apoptosis, overcomes resistance to standard chemotherapy agents and radiation therapy, and inhibits angiogenesis. Phase I study results established the antitumor activity of bortezomib, administered alone or in combination with standard chemotherapy agents, in patients with advanced hematologic malignancies or solid tumors, usually without additive toxicities. The results of phase II studies further supported the antitumor activity of bortezomib in patients with refractory or relapsed multiple myeloma and non-Hodgkin's lymphoma; less impressive results were observed in patients with stage IV renal cell cancer. Studies evaluating bortezomib in earlier stages of multiple myeloma, including first-line therapy, are under way. Evidence suggests that certain prognostic factors, such as older age and bone marrow containing more than 50% plasma cells, may be useful in predicting response and survival time in multiple myeloma patients receiving bortezomib. Further studies of bortezomib are needed to establish its full spectrum of activity, the ideal regimens for various tumor types, and clinically useful prognostic indicators that predict successful outcomes.
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PMID:Discovery, Development, and clinical applications of bortezomib. 1568 97

Bortezomib (PS-341, Velcade) is a novel, first-in-class proteasome inhibitor with antitumor activity against a number of hematologic and nonhematologic malignancies. Based on the results of phase II clinical trials, bortezomib received accelerated US Food and Drug Administration approval on May 13, 2003, for the treatment of multiple myeloma patients whose disease has progressed after they have received at least two prior conventional therapies. The results of phase III studies evaluating bortezomib as first- or second-line therapy, or in combination with other commonly prescribed therapies in multiple myeloma patients, are eagerly awaited. Studies assessing the antitumor effects of bortezomib in other hematologic malignancies and solid tumors are also under way. A thorough understanding of the pharmacology, pharmacodynamics, and pharmacokinetics of this novel compound is essential for appropriate prescribing and monitoring of bortezomib therapy. Bortezomib is rapidly distributed into tissues after administration of a single dose, with an initial plasma distribution half-life of less than 10 minutes, followed by a terminal elimination half-life of more than 40 hours. Maximum proteasome inhibition occurs within 1 hour and recovers close to baseline within 72 to 96 hours after administration. Bortezomib is primarily metabolized by oxidative deboronation to one of two inactive enantiomers that are further processed and eliminated, both renally and in bile. Bortezomib has been shown to be a substrate of several cytochrome P450 isoenzymes using in vitro systems. Adverse effects of bortezomib are generally mild and effectively managed with supportive care. Bortezomib should be administered with caution to patients with preexisting fluid retention and patients with baseline platelet counts of less than 70,000/microL. Dose reductions are recommended for patients experiencing peripheral neuropathy, grade 3 or higher nonhematologic toxicities, or grade 4 hematologic toxicities. Formal drug interaction studies have not been performed, but bortezomib has been administered in combination with a variety of antitumor agents without significant alterations to its pharmacokinetic or pharmacodynamic profile.
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PMID:Pharmacology, pharmacokinetics, and practical applications of bortezomib. 1568 98

Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its toxicity is manageable, and the most frequent adverse effects mainly consist of gastrointestinal symptoms, peripheral neuropathy, neuropatic pain, and thrombocytopenia. Severe liver toxicity has not been previously recognized. A patient with relapsed multiple myeloma who developed bortezomib-induced severe recurrent hepatitis is described. The importance of recognizing this rare potential toxicity is highlighted in order to discontinue this agent if liver adverse reaction is suspected.
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PMID:Bortezomib-induced severe hepatitis in multiple myeloma: a case report. 1573 79

Bortezomib [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (NMR) were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib, as the principal circulating metabolites were observed in vitro. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore.
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PMID:Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. 1576 13


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