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)

The proteasome is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the proteasome inhibitor bortezomib decreases proliferation, induces apoptosis, enhances the activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models in vitro and in vivo. Proteasome inhibition with bortezomib has specifically promoted apoptosis of tumor cells through the stabilization of p53, p21, p27, Bax, and IkappaBalpha, resulting in nuclear factor kappaB inhibition. Bortezomib was the first proteasome inhibitor to enter clinical trials. In two Phase II trials, SUMMIT and CREST, it was found that treatment with bortezomib, alone or in combination with dexamethasone, produced durable responses with meaningful survival benefits in patients with recurrent and/or refractory multiple myeloma. In the APEX Phase III trial, bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma. Clinical trials evaluating the safety and activity of bortezomib alone or in combination regimens with dexamethasone, doxorubicin, melphalan, prednisone, and/or thalidomide in the treatment of patients with newly diagnosed multiple myeloma have shown encouraging results. Preliminary studies suggest that bortezomib may serve as induction therapy before stem cell transplantation. Proteasome inhibition with bortezomib also has shown activity with manageable toxicity in mantle cell and other lymphomas, leukemias, and solid malignancies, including nonsmall cell lung carcinoma. Further studies with bortezomib as monotherapy and in combination regimens in the treatment of solid and hematologic malignancies are warranted.
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PMID:Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. 1617 3

More effective therapies are needed for non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Proteasome inhibitors are one class of molecularly targeted antineoplastic agents being investigated for these diseases. These agents block the activity of the 26S proteasome, which is responsible for the degradation of the vast majority of intracellular proteins and thus affect multiple signaling pathways within cells. Bortezomib is the first proteasome inhibitor to be evaluated in human studies and is approved for use in multiple myeloma. Bortezomib is now being investigated as a potential treatment for NSCLC and SCLC. Preclinical studies have shown that single-agent bortezomib causes growth inhibition and apoptosis in numerous NSCLC cell lines in vitro and has antitumor activity in vivo. Bortezomib affects the levels of several proteins known to be of significance in lung cancers. Studies of bortezomib in combination with other antitumor agents in vitro and in vivo demonstrate that these combination regimens can offer additive/synergistic effects compared with the single agents. Bortezomib has been investigated in combination with taxanes, gemcitabine, carboplatin, histone deactylase inhibitors, and other molecularly targeted agents in various NSCLC cell lines. The sequence of administration of the agents in preclinical combination regimens in vitro and in vivo has been shown to be of significance; further elucidation of the mechanism of efficacy of bortezomib in lung cancer is required. Numerous clinical studies have been carried out or are ongoing. Bortezomib has the potential to play a significant role in the future management of NSCLC and SCLC.
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PMID:Preclinical data with bortezomib in lung cancer. 1625 Sep 27

Proteasome inhibition is a novel approach to treating malignancy, and bortezomib is the first proteasome inhibitor in this class to be approved for clinical use. In preclinical studies, bortezomib caused cell cycle arrest and apoptosis in myeloma and lymphoma cell lines as well as in other neoplastic cell types. Phase I clinical trials established an optimal dosing strategy and demonstrated a manageable toxicity profile. Cyclical thrombocytopenia and peripheral neuropathy, which generally abate after cessation of treatment, are the most clinically significant toxicities. Two phase II trials, SUMMIT and CREST, demonstrated impressive activity with bortezomib 1.3 mg/m2 monotherapy in relapsed and refractory myeloma, with an impressive 35% response rate (complete+partial+minimal responses) in SUMMIT and a 50% response rate in CREST, using the rigorous European Group for Blood and Marrow Transplantation criteria. A recently completed phase III trial showed the significant clinical benefits of bortezomib over high-dose dexamethasone in patients with relapsed myeloma. Results of ongoing trials with bortezomib in the first-line treatment of myeloma have been extremely encouraging and have demonstrated the benefit of using bortezomib as part of an induction regimen prior to stem cell transplantation. Importantly, two clinical trials with bortezomib as monotherapy in refractory non-Hodgkin's lymphoma have shown impressive response rates, particularly in aggressive mantle cell lymphoma.
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PMID:Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic malignancies. 1629 74

Recent advanced developments in our understanding of cancer cell biology have begun to generate a host of new targets that are proving to be valuable substrates for new drug development. One example includes our ever-increasing understanding of the complex biology surrounding the ubiquitin-proteasome pathway. For years there have been a variety of compounds used in the laboratory that have been shown to inhibit the proteasome, though many of these compounds have proven to be relative non-specific inhibitors of intracellular and proteasome proteases. The recent synthesis of 1 novel inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibition represents a new approach for the treatment of many forms of cancer, especially select hematologic malignancies. Bortezomib has been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. In addition to myeloma, bortezomib has also shown promising activity in the treatment of select types of non-Hodgkin's lymphomas (NHLs). Several single-agent phase II clinical trials in patients with a host of different NHL histologies have demonstrated that bortezomib has reproducible activity in mantle-cell lymphoma (MCL) and follicular lymphoma (FL), with some suggestion of activity in marginal zone lymphoma. The promising activity in these smaller studies has led to a number of larger multicenter studies with bortezomib in combination with rituximab in MCL, FL, and marginal zone lymphoma. The collective early experience from these studies continues to support the activity of bortezomib in these histologies of NHL. Herein, some of the biologic rationale for using proteasome inhibitors in lymphoma as well as some of the clinical data from these promising studies are discussed.
Clin Lymphoma Myeloma 2005 Nov
PMID:Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma. 1635 24

Proteasome-mediated proteolysis is a mechanism for mediating important regulatory proteins within the cell. Proteins that have been targeted for degradation by the proteasome are convalently tagged with a poly-ubiquitin protein chain prior to be recognized by the 19S subunit of proteasome. This degradation system controls the expression of a wide variety of cellular targets including tumor suppressors such as p53, inhibitor of nuclear factor NFkappaB, cyclin-dependent kinase inhibitors such as p21 and p27. Because of these functions, the proteasome has become a new target for cancer treatment. The potent and selective proteasome inhibitor, PS-341 or Velcade was approved in the United States and launched in may 2003 for the treatment of multiple myeloma patients who have received at least two prior therapies. On April 2004, the European commission granted marketing authorization for Velcade with the same indication. The same year 2004, the Nobel Prize in chemistry was awarded to three researchers "for the discovery of ubitiquin-mediated protein degradation", a regulated process by which proteins are cleaved into peptides inside cells.
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PMID:[A new therapy with bortezomib, an oncologic medicinal product of the year 2004]. 1638 84

The ubiquitin-proteasome pathway is responsible for the vast majority of regulated eukaryotic intracellular proteolysis. Inhibition of the proteasome induces beneficial antitumour effects by blocking cell-cycle progression, inducing apoptosis and suppressing angiogenesis. Bortezomib is the first proteasome inhibitor to reach the clinical arena, where Phase I - III trials verified its activity against relapsed/refractory multiple myeloma. Testing is ongoing to determine bortezomib's role in front-line therapy of this plasma cell dyscrasia, as well as in non-Hodgkin's lymphoma, in which encouraging single-agent activity has been seen. Proteasome inhibition is also a rational strategy to overcome chemoresistance and induce chemosensitisation. Combinations of bortezomib and other agents have enhanced efficacy, and additional studies are probing the activity of several regimens in lymphoid and myeloid malignancies. The current state of knowledge about the activity of bortezomib, both alone and in combination with standard chemotherapeutics, as part of the emerging armamentarium against haematological malignancies is reviewed.
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PMID:Targeting the proteasome as a therapeutic strategy against haematological malignancies. 1643 92

Multiple myeloma is a malignant process of the plasma cell. There is no cure for this disease and at present the focus is to manage the disease as a chronic process to achieve a good quality of life. Hopefully, with the advancement in the understanding of the pathophysiology of the disease, target therapy should allow for the control of multiple myeloma, its prevention, and/or the reversal of organ damage; therefore prolonging survival. Proteasome inhibitors and immune modulators are the first of new therapies that target the malignant plasma cell microenvironment. In this review, different aspects of these agents are discussed.
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PMID:Pharmacotherapy of multiple myeloma. 1655 91

Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies. The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.
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PMID:Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas. 1657 48

Therapeutic options for patients with myeloma are a rapidly advancing area of research due in part to an increase in the understanding of myeloma biology as well as the development of novels agents. Proteasome inhibition is a novel modality for the treatment of patients with myeloma. Bortezomib, a novel proteasome inhibitor, was effective in a broad range of tumor cell lines in preclinical testing. In phase I trials, bortezomib was noted to be active in patients with multiple myeloma and lymphoma. This led to several multicenter trials confirming the safety and efficacy of bortezomib for patients with relapsed and refractory myeloma. Most recently, a large randomized phase III trial comparing bortezomib with high-dose dexamethasone demonstrated that bortezomib had an improved response rate, duration of remission and overall survival advantage in the setting of relapsed disease. These findings have led investigators to study proteasome inhibition with conventional chemotherapy and other novel agents. In addition, several recently completed and ongoing studies are evaluating the role of bortezomib in the initial treatment of myeloma. The success of proteasome inhibition in the treatment of myeloma is a model for effective translation of preclinical research into tangible clinical benefits for patients with cancer.
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PMID:Proteasome inhibition: novel therapy for multiple myeloma. 1660 73

Inhibition of p38 kinase blocks the production of tumor-promoting factors in the multiple myeloma (MM) bone marrow microenvironment. Proteasome inhibitors MG132 and bortezomib have been shown to have direct cytotoxic effects on MM cells. We show that a selective inhibitor of p38alpha, SCIO-469, enhances the ability of MG132 and bortezomib to induce the apoptosis of MM cells. Previously, we showed that p38 inhibition with SCIO-469 enhances MM cytotoxicity of bortezomib by inhibiting the transient expression and phosphorylation of Hsp27, a downstream target of p38. Here we show that continued treatment of MM cells with bortezomib leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis. Furthermore, we show that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and downregulation of Bcl-X(L) and Mcl-1. In a mouse xenograft plasmacytoma model of MM, we found that inhibiting p38 augments the effects of bortezomib in decreasing MM tumor growth in vivo. Thus, in addition to its role in suppressing an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic factors in MM cells, suggesting great potential for co-therapy.
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PMID:Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. 1661 27


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