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 ubiquitin-proteasome system plays a crucial role in eukaryotic cells in maintaining protein homeostasis. Through the disruption of a variety of pathways and cell cycle checkpoints, proteasome inhibition leads to apoptosis and in experimental models can overcome chemoresistance. Bortezomib is the first of its class of proteasome inhibitors tested in humans that showed promising activity in several tumor types, and especially in hematologic malignancies, in phase I studies. The remarkable results obtained in phase II studies in multiple myeloma (MM) led to its fast-track approval by the US Food and Drug Administration in May 2003 for relapsed MM. More recent observation also revealed promising activity in non-Hodgkin's lymphoma. This review will explore the rationale for the use of bortezomib in hematologic malignancies as well as provide an update on the results of ongoing studies and future directions for the use of this new agent in hematologic malignancies. The mechanism of action of bortezomib and its nonoverlapping toxicity profile make it a very appealing drug for combination with other chemotherapeutic or biologic agents. Bortezomib represents an excellent example of how progress in understanding the biology of cancer cells can impact clinical practice and lead toward a new era of rational therapeutics.
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PMID:Update on the proteasome inhibitor bortezomib in hematologic malignancies. 1507 15

The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials. Efficacy and safety results from a phase 2 clinical trial contributed to approval of bortezomib for use in patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies and have demonstrated disease progression on their last therapy.
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PMID:The development of proteasome inhibitors as anticancer drugs. 1514 49

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer.
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PMID:Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. 1514 7

Multiple myeloma (MM) represented 14% of new haematological malignancies in the US in 2003 and almost 19% of anticipated deaths. Treatment with standard chemotherapy has resulted in a median survival of about 3 years and despite the improvements in survival seen with the use of intensive therapy supported by autologous stem cell transplantation, MM remains incurable; hence, new therapeutic strategies are urgently needed. One novel approach to the treatment of MM is the use of proteasome inhibitors. Proteasomes are ubiquitous protease complexes involved in diverse aspects of cell biology, such as protein homeostasis, cell cycle progression, apoptosis and inflammation, as well as resistance to antineoplastic therapy. The first-in-class proteasome inhibitor, bortezomib was recently approved in the US for the treatment of patients with MM who have received at least two prior therapies and are progressing on their last therapy. Its use in earlier-stage MM, other haematological malignancies and in solid tumours as monotherapy and in combination therapy is currently under investigation.
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PMID:A review of the proteasome inhibitor bortezomib in multiple myeloma. 1516 77

The dipeptide boronic acid analogue VELCADE (Bortezomib; formerly known as PS-341, LDP-341 and MLM341) is a potent and selective inhibitor of the proteasome, a multicatalytic enzyme that mediates many cellular regulatory signals by degrading regulatory proteins or their inhibitors. The proteasome is, thus, a potential target for pharmacological agents. Bortezomib, the first proteasome inhibitor to reach clinical trials, has shown in vitro and in vivo activity against a variety of malignancies, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer. The drug is rapidly cleared from the vascular compartment, but a novel pharmacodynamic assay has shown that bortezomib--mediated proteasome blockade is dose-dependent and reversible. Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies.
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PMID:Development of the proteasome inhibitor Velcade (Bortezomib). 1519 12

Bortezomib (PS-341, Velcade, Millennium Pharmaceuticals, Cambridge, MA) is a novel inhibitor of the proteasome. The proteasome plays a critical role in the degradation and, therefore, regulation of many proteins involved in cell cycle regulation, apoptosis, and angiogenesis. Bortezomib inhibits the growth of lung cancer cell lines in vitro and in vivo in athymic nude mouse xenografts. Bortezomib produces a G(2)-M arrest, increases in cyclin A and cyclin B, increases in p21, and increases apoptosis in these preclinical models. Phase I studies established that a dose of 1.4 mg/m(2) given i.v. on days 1, 4, 8, and 11 of a 3-week cycle produced acceptable toxicity and serum levels that resulted in proteasome inhibition. Phase II studies showed high-response rates in refractory multiple myeloma. These response rates were sufficiently high to allow accelerated approval of bortezomib by the Food and Drug Administration for this indication. Phase II trials in both non-small cell lung cancer and small cell lung cancer are in progress. A number of Phase I combination studies are also underway. Hopefully, bortezomib will show sufficient activity in lung cancer to improve survival in this dread disease.
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PMID:The potential role of proteasome inhibitors in the treatment of lung cancer. 1521 71

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non-Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.
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PMID:Proteasome inhibition in hematologic malignancies. 1522 57

The elucidation of detailed new signaling pathways in normal cells and how their perturbation contributes to the development of the malignant phenotype has created innumerable venues for the development of novel drugs that can affect these targets in therapeutically meaningful ways. For example, our understanding of the complex biology underlying the ubiquitin-proteasome pathway in normal cells has recently led to the identification of specific agents capable of affecting this biology. Intuitively, one would not presume that inhibiting such a ubiquitous and essential biologic process, such as the ubiquitin-proteasome pathway, would lead to a new therapeutic strategy in cancer patients, although empirical evidence has suggested otherwise. The proteasome is a complex structure of many proteins, some of which are specific proteases, that play a critical role in regulating the balance of intracellular protein. Bortezomib, formerly known as PS-341, is a very potent and selective inhibitor of the chymotryptic-like enzymatic function residing in the 26S proteasome. Inhibition of this particular enzymatic activity has now been associated with an enormous panoply of different biologic effects, including everything from the regulation of nuclear factor-kappaB to the stabilization of cell-cycle regulatory proteins and the induction of apoptosis through the upregulation of specific proapoptotic proteins. Inhibiting this particular enzymatic function has now been associated with sometimes dramatic clinical effects in a variety of hematologic malignancies, including multiple myeloma and non-Hodgkin's lymphoma. This activity has led to the recent US Food and Drug Administration approval of bortezomib for the treatment of relapsed or refractory multiple myeloma. This activity has also spawned several clinical studies that have now clearly established activity in a host of different lymphoma subtypes, including the challenging mantle cell lymphomas. These data are simply the tip of the iceberg and will no doubt continue to provide fodder for many years of innovative scientific and clinical development. This development will likely lead to the eventual integration of this promising new class of molecules into the mainstream treatment of many hematologic malignancies, including myeloma and hopefully several different non-Hodgkin's lymphomas. Understanding how precisely to integrate these novel compounds will require us to learn more regarding the array of different biologic effects proteasome inhibitors have on the cell and how these effects can be further augmented with conventional chemotherapy drugs. The story is testament to the value of recognizing the importance of empiric observations in clinical and preclinical investigations.
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PMID:The emerging role of bortezomib in the treatment of indolent non-Hodgkin's and mantle cell lymphomas. 1523 4

The 26S proteasome is an adenosine triphosphate-dependent multicatalytic protease that is responsible for most nonlysosomal intracellular protein degradation. To be selected for proteasomal degradation, proteins must be previously tagged with a polyubiquitin chain, which is then recognized by the proteasome; the ubiquitin chain is removed by isopeptidases and the protein is hydrolysed to small polypeptides. In addition to removing damaged/unnecessary proteins, the proteasome is also an important mechanism of regulation of some key regulatory proteins and their inhibitors. This regulation is crucial for the control of many cellular processes, including activation of transcription factors, cell cycle progression, and apoptosis. The critical role of the ubiquitin-proteasome pathway in tumor cells has led to the investigation of proteasome inhibition as a potential anticancer therapy. The dipeptide boronic acid analogue bortezomib, formerly known as PS-341, is a potent, highly selective, and reversible proteasome inhibitor. The first drug of this class to be used in the clinical setting, it has recently been approved by the US Food and Drug Administration for the treatment of relapsed and refractory multiple myeloma and is currently being tested in clinical trials for the treatment of a wide variety of malignancies. This article provides a summary of the biology of the ubiquitin-proteasome pathway, reviews the available preclinical and clinical data of proteasome inhibition as a therapeutic strategy in breast cancer, and discusses future combination regimens involving bortezomib.
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PMID:Targeting the ubiquitin-proteasome pathway in breast cancer. 1524 20

Bortezomib, one of the proteasome inhibitors, has been approved in the United States for multiple myeloma as a second-line chemotherapy. In Japan, bortezomib has been used for for phase I clinical trials for multiple myeloma. As the action mechanism, it has been proposed that bortezomib inhibits NF-kappaB via IkappaB alpha. It also demonstrated positive results for non-Hodgkin's lymphoma and non-small cell lung cancer, but not for colorectal cancer or chronic lymphocytic leukemia. The mechanism of drug resistance has been well analized. Bortezomib is very effective but still induces adverse effects including hypotension especially when there is an overdose. Medical oncologists or hematology/oncologists must exert due caution.
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PMID:[Proteasome inhibitors]. 1527 75


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