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)

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 [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

Normal cellular functioning requires processing of proteins regulating cell cycle, growth, and apoptosis. The ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation. Specifically, the 26S proteasome is a multienzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death. Because cancer cells are more highly proliferative than normal cells, their rate of protein translation and degradation is also higher. This notion led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Ongoing studies are examining other novel proteasome inhibitors, in addition to bortezomib, for the treatment of MM and other cancers.
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PMID:Proteasome inhibition in multiple myeloma: therapeutic implication. 1582 85

Proteasome inhibitors have emerged as promising anticancer therapeutic agents. Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies and has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. However, the molecular mechanisms of bortezomib-mediated apoptosis remain unclear. To characterize the mechanisms of apoptosis induction by proteasome inhibitors, we examined levels of Bcl-2 protein family members (Bik/NBK, Bax, Bak, Bcl-2, and Bcl-XL), release of cytochrome c, and activation of caspase-9 and -3 in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human lung cancer cell line H1299; and human ovarian cancer cell line SKOV3 after they were treated with bortezomib. The result showed that bortezomib induced rapid accumulation of Bik/NBK but not other Bcl-2 family members in all six cell lines. Bortezomib-mediated Bik/NBK accumulation and apoptosis were also observed in human embryonic kidney cells 293 and normal human bronchial epithelial cells. Moreover, dramatic Bik/NBK accumulation and apoptosis induction were observed when cells were treated with proteasome inhibitor MG132 and calpain inhibitor I (ALLN). Furthermore, no detectable changes in IkappaBalpha levels or in NFkappaB functionality were found after treatment with bortezomib. Finally, Bik/NBK accumulation was caused by stabilization of the protein from degradation and was associated with bortezomib cytotoxicity and apoptosis induction. Pretreatment of DLD1 cells with Bik/NBK siRNA reduced bortezomib-mediated Bik/NBK accumulation and cell death. Our results suggested that Bik/NBK is one of the mediators of proteasome inhibitor-induced apoptosis.
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PMID:Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. 1582 29

Proteasome inhibitors represent novel anti-cancer drugs which interact with the proteasome-ubiquitin pathway. The 26S proteasome is a multicatalytic threonine protease with three distinct catalytic activities. It is responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of short- and some long-living proteins required for regulation of various cellular functions. Subsequently, the inhibition of the proteasomal function results in stabilization and accumulation of its substrates, which notably include cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, tumor suppressor proteins and proto-oncogenes. This results in confounding signals in the cell inducing cell cycle arrest and activation of apoptotic programs. Acting on transcriptional factor NF-kappaB, which is upregulated in some tumors undergoing chemotherapy or irradiation and downregulated by proteasome inhibition, a significant chemosensitization and consequently synergistic effects concerning the anti-tumor activity could be achieved. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. At present, other trials examine the activity in a variety of solid tumors and hematological malignancies. This paper reviews preclinical and clinical results.
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PMID:Proteasome: an emerging target for cancer therapy. 1584 12

Proteasome inhibitors, such as the dipeptide boronic acid bortezomib, are emerging as important tools in the treatment of the fatal hematologic malignancy multiple myeloma. Despite the recent US Food and Drug Administration approval of bortezomib (PS341, Velcade) for the treatment of refractory multiple myeloma, many of the basic pharmacologic parameters of bortezomib and its mode of action on myeloma cells remain to be determined. We describe the synthesis and use of a cell-permeant active site-directed probe, which allows profiling of proteasomal activities in living cells. When we compared proteasome activity patterns in cultured cells and crude cell extracts with this probe, we observed substantial differences, stressing the importance for bioassays compatible with live cells to ensure accuracy of such measurements. Using this probe, we investigated the in vivo subunit specificities of bortezomib and another inhibitor, MG132.
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PMID:Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. 1584 63

The proteasome inhibitor bortezomib (also known as PS-341/Velcade) is a dipeptidyl boronic acid that has recently been approved for use in patients with multiple myeloma. Bortezomib inhibits the activity of the 26S proteasome and induces cell death in a variety of tumor cells; however, the mechanism of cytotoxicity is not well understood. In this report, oligonucleotide microarray analysis of the 8226 multiple myeloma cell line showed a predominant induction of gene products associated with the endoplasmic reticulum secretory pathway following short-term, high-dose exposure to bortezomib. Examination of mediators of endoplasmic reticulum stress-induced cell death showed specific activation of caspase 12, as well as of caspases 8, 9, 7, and 3, and cleavage of bid. Treatment of myeloma cells with bortezomib also showed disregulation of intracellular Ca2+ as a mechanism of caspase activation. Cotreatment with a panel of Ca2+-modulating agents identified the mitochondrial uniporter as a critical regulatory factor in bortezomib cytotoxicity. The uniporter inhibitors ruthenium red and Ru360 prevented caspase activation and bid cleavage, and almost entirely inhibited bortezomib-induced cell death, but had no effect on any other chemotherapeutic drug examined. Additional Ca2+-modulating agents, including 2-amino-ethoxydiphenylborate, 1,2-bis (o-aminophenoxy) ethane-tretraacetic acid (acetoxymethyl) ester, and dantrolene, did not alter bortezomib cytotoxicity. Analysis of intracellular Ca2+ showed that the ruthenium-containing compounds inhibited Ca2+ store loading and abrogated the desensitized capacitative calcium influx associated with bortezomib treatment. These data support the hypothesis that intracellular Ca2+ disregulation is a critical determinant of bortezomib cytotoxicity.
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PMID:Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. 1586 81

The fast-track approval of a proteasome inhibitor, PS-341, to treat multiple myeloma spurred a wave of interest in both the proteasome itself and small-molecule compounds blocking its activities. Besides being candidates for drugs against cancer, autoimmune diseases, inflammation, or stroke, specific proteasome inhibitors are indispensable tools for biochemical and cell biology investigations of the proteasome and proteasome-ubiquitin system. Numerous synthetic peptide derivatives, such as boronates, epoxides, aldehydes, vinyl sulfones, cyclic peptides, and lactones, block the N-terminal threonine-type active centers of the enzyme, halting the cleavage of proteasomal protein substrates both in vitro and in vivo. Because some of the proteasomal inhibitors exhibit a high specificity toward only one particular type of an active center of the proteasome, they constitute valuable probes for testing the mechanism of proteolysis catalyzed by the enzyme. In this chapter we discuss the most common applications of available proteasome inhibitors. In addition to the best-known competitive inhibitors, we also describe the benefits from the use of allosteric inhibitors, which induce distinct but less understood in vitro and in vivo effects on the proteasomal machinery. Finally, we present the application of the basic biochemical procedures to decipher the mechanism of interactions of a novel compound with the proteasome.
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PMID:Small-molecule inhibitors of proteasome activity. 1591 22

Inhibitors of the proteasome have long been used in studies of protein turnover, but in a notable example of successful translational research they have made the leap from the laboratory into the clinical arena. The proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341), has recently been approved in the United States for treatment of patients with multiple myeloma who have received at least two prior therapies, and have demonstrated disease progression on their last therapy. Furthermore, studies of this agent in other hematologic malignancies and solid tumors are underway, and other proteasome inhibitors for clinical use are under development as well. This chapter provides the reader with guidelines for the optimal clinical administration of VELCADE for its currently approved indication, as well as some suggestions for subsequent management of treatment-related events in these patients.
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PMID:Proteasome inhibitors in cancer therapy. 1591 44


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