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Kenneth C Anderson - One of the best experts on this subject based on the ideXlab platform.
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synergistic anti myeloma activity of the Proteasome Inhibitor marizomib and the imid immunomodulatory drug pomalidomide
British Journal of Haematology, 2015Co-Authors: Deepika Sharma Das, Paul G. Richardson, Arghya Ray, Yan Song, Mohit Trikha, Dharminder Chauhan, Kenneth C AndersonAbstract:The Proteasome Inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel Proteasome Inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment of RRMM. Here, we demonstrate that combining low concentrations of marizomib with pomalidomide induces synergistic anti-MM activity. Marizomib plus pomalidomide-induced apoptosis is associated with: (i) activation of caspase-8, caspase-9, caspase-3 and PARP cleavage, (ii) downregulation of cereblon (CRBN), IRF4, MYC and MCL1, and (iii) suppression of chymotrypsin-like, caspase-like, and trypsin-like Proteasome activities. CRBN-siRNA attenuates marizomib plus pomalidomide-induced MM cells death. Furthermore, marizomib plus pomalidomide inhibits the migration of MM cells and tumour-associated angiogenesis, as well as overcomes cytoprotective effects of bone marrow microenvironment. In human MM xenograft model studies, the combination of marizomib and pomalidomide is well tolerated, inhibits tumour growth and prolongs survival. These preclinical studies provide the rationale for on-going clinical trials of combined marizomib and pomalidomide to improve outcome in patients with RRMM.
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the investigational Proteasome Inhibitor ixazomib for the treatment of multiple myeloma
Future Oncology, 2015Co-Authors: Paul G. Richardson, Kenneth C Anderson, Philippe Moreau, Jacob P Laubach, Neeraj Gupta, Ai Min Hui, Jesus San F Miguel, Shaji KumarAbstract:Ixazomib is an investigational, reversible 20S Proteasome Inhibitor. It is the first oral Proteasome Inhibitor under clinical investigation in multiple myeloma (MM). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, ixazomib (MLN2238). Preclinical studies have demonstrated antitumor activity in MM cell lines and xenograft models. In Phase I/II clinical studies ixazomib has had generally manageable toxicities, with limited peripheral neuropathy observed to date. Preliminary data from these studies indicate ixazomib is active as a single agent in relapsed/refractory MM and as part of combination regimens in newly diagnosed patients. Phase III studies in combination with lenalidomide-dexamethasone are ongoing.
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A novel Proteasome Inhibitor NPI-0052 as an anticancer therapy
British Journal of Cancer, 2006Co-Authors: Dharminder Chauhan, Teru Hideshima, Kenneth C AndersonAbstract:Proteasome Inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel Proteasome Inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/refractory MM patients.
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Proteasome Inhibitor drugs on the rise.
Cancer research, 2006Co-Authors: Claudio A. P. Joazeiro, Kenneth C Anderson, Tony HunterAbstract:In May 2003, the U.S. Food and Drug Administration granted the Proteasome Inhibitor bortezomib (Velcade) fast-track status for the treatment of multiple myeloma. This landmark represented the first approval of a drug targeting the ubiquitin-Proteasome system (UPS) for any indication. More recently, at the AACR Special Conference "Ubiquitin and Cancer: From Molecular Targets and Mechanisms to the Clinic" (Orlando, FL, January 18-22, 2006), it became evident that drug discovery in the UPS is experiencing another round of great excitement. The reason--new clinical applications found for bortezomib, along with the promised success of new types of Proteasome Inhibitors reaching the clinic.
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Proteasome Inhibitor therapy in multiple myeloma
Molecular Cancer Therapeutics, 2005Co-Authors: Dharminder Chauhan, Constantine S Mitsiades, Paul G. Richardson, Teru Hideshima, Kenneth C AndersonAbstract:Multiple myeloma remains incurable despite available therapies, and novel therapies that target both tumor cell and bone marrow microenvironment are urgently needed. Preclinical in vitro and in vivo studies show remarkable anti-multiple myeloma activity of the Proteasome Inhibitor bortezomib/PS-341 even in multiple myeloma cells refractory to multiple prior therapies, including dexamethasone, melphalan, and thalidomide. Based on these findings, the U.S. Food and Drug Administration recently approved the first Proteasome Inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of relapsed/refractory multiple myeloma. Bortezomib therapy has set an outstanding example of translational research in the field of oncology. Genomics and proteomic studies further provide rationale for combining bortezomib with conventional and novel agents to inhibit multiple myeloma growth, overcome drug resistance, reduce attendant toxicity, and improve patient outcome in multiple myeloma.
Toshiyuki Sakai - One of the best experts on this subject based on the ideXlab platform.
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Proteasome Inhibitor MG132 induces Death Receptor 5 through CHOP in prostate cancer cell
Cancer Research, 2006Co-Authors: Tatsushi Yoshida, Miki Wakada, Takumi Shiraishi, Susumu Nakata, Yoichi Mizutani, Tsuneharu Miki, Toshiyuki SakaiAbstract:2385 TNF-related apoptosis-inducing ligand (TRAIL) is one of promising candidates for cancer therapeutics due to its ability to induce apoptosis in cancer cells with little or no toxicity in normal cells. However, some tumor types exhibit resistance to TRAIL. Thus it is important to overcome this resistance. Combined treatment with a Proteasome Inhibitor and TRAIL is a promising strategy to overcome TRAIL resistance in cancer cells. Proteasome Inhibitors induce the expression of Death Receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism of DR5 up-regulation has not been elucidated. In this study, we report that CHOP is a regulator of DR5 induction by Proteasome Inhibitor MG132. First, we show that the combination of MG132 and TRAIL effectively induced apoptosis even in hormone refractory prostate cancer DU145 cells. DU145 cells have a mutation of tumor suppressor p53 gene. Therefore our result suggests that the combination of MG132 and TRAIL is efficacious in malignant tumors carrying p53 mutation. MG132 induced DR5 expression at a protein and mRNA level in DU145 cells, indicating that the induction was also independent of p53. Furthermore, MG132 increased DR5 promoter activity. Using a series of deletion-mutant plasmids containing DR5 promoters of various sizes, we found that MG132 stimulated the promoter activity through the region of - 289 to - 253. This region contained a CHOP-binding site. Site-directed mutation of the site abrogated the promoter activity enhanced by MG132. An electrophoretic mobility shift assay demonstrated that CHOP directly bound to the MG132-responsive site on the DR5 promoter. Expression of the CHOP protein was increased with MG132 along with DR5 up-regulation. In addition, MG132 also increased CHOP mRNA and promoter activity. Furthermore, CHOP siRNA attenuated the DR5 up-regulation due to MG132. These results indicate that the Proteasome Inhibitor MG132 induces DR5 expression through CHOP up-regulation.
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Proteasome Inhibitor MG132 induces death receptor 5 through CCAAT/enhancer-binding protein homologous protein.
Cancer Research, 2005Co-Authors: Tatsushi Yoshida, Mano Horinaka, Miki Wakada, Takumi Shiraishi, Susumu Nakata, Yoichi Mizutani, Tsuneharu Miki, Toshiyuki SakaiAbstract:Combined treatment with a Proteasome Inhibitor and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising strategy for cancer therapy. Proteasome Inhibitors induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism of DR5 up-regulation has not been elucidated. In this study, we report that CCAAT/enhancer-binding protein homologous protein (CHOP) is a regulator of DR5 induction by Proteasome Inhibitor MG132. MG132 induced DR5 expression at a protein and mRNA level in prostate cancer DU145 cells. Furthermore, MG132 increased DR5 promoter activity. Using a series of deletion mutant plasmids containing DR5 promoters of various sizes, we found that MG132 stimulated the promoter activity via the region of −289 to −253. This region contained a CHOP-binding site. Site-directed mutation of the site abrogated the promoter activity enhanced by MG132. An electrophoretic mobility shift assay showed that CHOP directly bound to the MG132-responsive site on the DR5 promoter. Expression of the CHOP protein was increased with MG132 along with DR5 up-regulation. Furthermore, CHOP small interfering RNA attenuated the DR5 up-regulation due to MG132. These results indicate that the Proteasome Inhibitor MG132 induces DR5 expression through CHOP up-regulation.
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Proteasome Inhibitor mg132 induces death receptor 5 through ccaat enhancer binding protein homologous protein
Cancer Research, 2005Co-Authors: Tatsushi Yoshida, Mano Horinaka, Miki Wakada, Takumi Shiraishi, Susumu Nakata, Yoichi Mizutani, Tsuneharu Miki, Toshiyuki SakaiAbstract:Combined treatment with a Proteasome Inhibitor and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising strategy for cancer therapy. Proteasome Inhibitors induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism of DR5 up-regulation has not been elucidated. In this study, we report that CCAAT/enhancer-binding protein homologous protein (CHOP) is a regulator of DR5 induction by Proteasome Inhibitor MG132. MG132 induced DR5 expression at a protein and mRNA level in prostate cancer DU145 cells. Furthermore, MG132 increased DR5 promoter activity. Using a series of deletion mutant plasmids containing DR5 promoters of various sizes, we found that MG132 stimulated the promoter activity via the region of −289 to −253. This region contained a CHOP-binding site. Site-directed mutation of the site abrogated the promoter activity enhanced by MG132. An electrophoretic mobility shift assay showed that CHOP directly bound to the MG132-responsive site on the DR5 promoter. Expression of the CHOP protein was increased with MG132 along with DR5 up-regulation. Furthermore, CHOP small interfering RNA attenuated the DR5 up-regulation due to MG132. These results indicate that the Proteasome Inhibitor MG132 induces DR5 expression through CHOP up-regulation.
Yasuo Matsumura - One of the best experts on this subject based on the ideXlab platform.
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A Proteasome Inhibitor lessens the increased aortic endothelin-1 content in deoxycorticosterone acetate-salt hypertensive rats
European journal of pharmacology, 1998Co-Authors: Hisako Okamoto, Masanori Takaoka, Mio Nishioka, Mamoru Ohkita, Makoto Itoh, Yasuo MatsumuraAbstract:Abstract Deoxycorticosterone acetate (DOCA)-salt-treated rats developed marked hypertension after 4 weeks with an increase in aortic endothelin-1. Treatment of DOCA-salt hypertensive rats with a Proteasome Inhibitor, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, significantly reduced the elevation in systolic blood pressure and the effect was accompanied by a decrease in aortic endothelin-1 content. Thus, a Proteasome-dependent proteolytic pathway appears to play an important role in the enhanced production of endothelin-1 in blood vessels and the consequent increase in blood pressure in this model of hypertension.
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Antihypertensive effect of a Proteasome Inhibitor in DOCA-salt hypertensive rats.
Life Sciences, 1998Co-Authors: Masanori Takaoka, Hisako Okamoto, Makoto Ito, Mio Nishioka, Satomi Kita, Yasuo MatsumuraAbstract:Abstract To search for a possible role for vascular Proteasome in hypertension, we examined changes in Proteasome level in aorta of deoxycorticosterone acetate (DOCA)-salt hypertensive rats and evaluated the antihypertensive effect of a Proteasome Inhibitor, N -benzyloxycarbonyl-Ile-Glu-( O-t -Bu)-Ala-leucinal (PSI). Two weeks after the start of DOCA-salt treatment, the rats, with systolic blood pressure being 154 ± 5 mmHg, were randomly divided into two groups and were given PSI or its vehicle for 2 weeks. Vehicle-treated DOCA-salt rats developed marked hypertension after 4 weeks (198 ± 9 mmHg), with increases in aortic Proteasome activity and content. The systolic blood pressure was positively correlated with both the content and activity of aortic Proteasome. The administration of PSI to DOCA-salt hypertensive rats suppressed the elevation of systolic blood pressure (144 ± 4 mmmHg), accompanied by decreases in aortic Proteasome activity and content. These results suggest that Proteasome production in vascular tissues is increased in DOCA-salt hypertensive rats, and that PSI exhibits antihypertensive effect in this experimental hypertensive model. Thus, the findings indicate the pathophysiological importance of increased vascular Proteasome in the development of DOCA-salt hypertension.
Huaqin Wang - One of the best experts on this subject based on the ideXlab platform.
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Proteasome Inhibitor mg132 induces bag3 expression through activation of heat shock factor 1
Journal of Cellular Physiology, 2009Co-Authors: Zhenxian Du, Yifu Guan, Xin Meng, Hai-yan Zhang, Huaqin WangAbstract:BAG3 protein, a member of the BAG co-chaperones family, sustains cell survival in a variety of normal and neoplastic cell types, via its interaction with a variety of partners, such as the heat shock protein (HSP) 70, Bcl-2, Raf-1 and others. Expression of BAG3 is induced by some stressful stimuli, such as heat shock, heavy metal exposure. We have reported that Proteasome Inhibitors can also induce BAG3 expression at the transcriptional level and the induction of BAG3 compromises Proteasome Inhibitors-mediated apoptosis. However, the molecular mechanism of BAG3 upregulation has not been elucidated. In the current study, we provide evidence that heat shock transcription factor 1 (HSF1) is involved in BAG3 induction by Proteasome Inhibitor MG132. Using a series of varying lengths of 5′-flanking region of the BAG3 gene into luciferase reporter vectors, we found that MG132 stimulated the promoter activity via the −326/−233 and −825/−689 regions, which contains one putative heat shock-responsive element (HSE) for HSF1-binding, respectively. Site-directed deletion of the sites abrogated the enhanced reporter activity in response to MG132 treatment. Chromatin immunoprecipitation assay demonstrated that HSF1 directly bound to the MG132-responsive site on the BAG3 promoter. Activation of HSF1 occurred with MG132 along with BAG3 upregulation. Furthermore, knockdown HSF1 by small interfering RNA attenuated the BAG3 upregulation due to MG132.These results indicate that the Proteasome Inhibitor MG132 induces BAG3 expression through HSF1 activation. J. Cell. Physiol. 218: 631–637, 2009. © 2008 Wiley-Liss, Inc.
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role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by Proteasome Inhibitor in thyroid cancer cells
BMC Cancer, 2009Co-Authors: Hai-yan Zhang, Xin Meng, Yifu Guan, Huaqin WangAbstract:The Proteasome Inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Although bortezomib is known to be a selective Proteasome Inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. Proteasome activity, intracellular glutathione (GSH) and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR. At concentrations that effectively inhibited Proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH) and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death. GSH protects cells from Proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to Proteasome inhibition-induced apoptosis.
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Proteasome Inhibitor MG132 induces BAG3 expression through activation of heat shock factor 1.
Journal of cellular physiology, 2009Co-Authors: Hai-yan Zhang, Yifu Guan, Xin Meng, Yan-yan Gao, Ren-long Zou, Bao-qin Liu, Huaqin WangAbstract:BAG3 protein, a member of the BAG co-chaperones family, sustains cell survival in a variety of normal and neoplastic cell types, via its interaction with a variety of partners, such as the heat shock protein (HSP) 70, Bcl-2, Raf-1 and others. Expression of BAG3 is induced by some stressful stimuli, such as heat shock, heavy metal exposure. We have reported that Proteasome Inhibitors can also induce BAG3 expression at the transcriptional level and the induction of BAG3 compromises Proteasome Inhibitors-mediated apoptosis. However, the molecular mechanism of BAG3 upregulation has not been elucidated. In the current study, we provide evidence that heat shock transcription factor 1 (HSF1) is involved in BAG3 induction by Proteasome Inhibitor MG132. Using a series of varying lengths of 5'-flanking region of the BAG3 gene into luciferase reporter vectors, we found that MG132 stimulated the promoter activity via the -326/-233 and -825/-689 regions, which contains one putative heat shock-responsive element (HSE) for HSF1-binding, respectively. Site-directed deletion of the sites abrogated the enhanced reporter activity in response to MG132 treatment. Chromatin immunoprecipitation assay demonstrated that HSF1 directly bound to the MG132-responsive site on the BAG3 promoter. Activation of HSF1 occurred with MG132 along with BAG3 upregulation. Furthermore, knockdown HSF1 by small interfering RNA attenuated the BAG3 upregulation due to MG132.These results indicate that the Proteasome Inhibitor MG132 induces BAG3 expression through HSF1 activation.
Paul G. Richardson - One of the best experts on this subject based on the ideXlab platform.
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synergistic anti myeloma activity of the Proteasome Inhibitor marizomib and the imid immunomodulatory drug pomalidomide
British Journal of Haematology, 2015Co-Authors: Deepika Sharma Das, Paul G. Richardson, Arghya Ray, Yan Song, Mohit Trikha, Dharminder Chauhan, Kenneth C AndersonAbstract:The Proteasome Inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel Proteasome Inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment of RRMM. Here, we demonstrate that combining low concentrations of marizomib with pomalidomide induces synergistic anti-MM activity. Marizomib plus pomalidomide-induced apoptosis is associated with: (i) activation of caspase-8, caspase-9, caspase-3 and PARP cleavage, (ii) downregulation of cereblon (CRBN), IRF4, MYC and MCL1, and (iii) suppression of chymotrypsin-like, caspase-like, and trypsin-like Proteasome activities. CRBN-siRNA attenuates marizomib plus pomalidomide-induced MM cells death. Furthermore, marizomib plus pomalidomide inhibits the migration of MM cells and tumour-associated angiogenesis, as well as overcomes cytoprotective effects of bone marrow microenvironment. In human MM xenograft model studies, the combination of marizomib and pomalidomide is well tolerated, inhibits tumour growth and prolongs survival. These preclinical studies provide the rationale for on-going clinical trials of combined marizomib and pomalidomide to improve outcome in patients with RRMM.
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the investigational Proteasome Inhibitor ixazomib for the treatment of multiple myeloma
Future Oncology, 2015Co-Authors: Paul G. Richardson, Kenneth C Anderson, Philippe Moreau, Jacob P Laubach, Neeraj Gupta, Ai Min Hui, Jesus San F Miguel, Shaji KumarAbstract:Ixazomib is an investigational, reversible 20S Proteasome Inhibitor. It is the first oral Proteasome Inhibitor under clinical investigation in multiple myeloma (MM). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, ixazomib (MLN2238). Preclinical studies have demonstrated antitumor activity in MM cell lines and xenograft models. In Phase I/II clinical studies ixazomib has had generally manageable toxicities, with limited peripheral neuropathy observed to date. Preliminary data from these studies indicate ixazomib is active as a single agent in relapsed/refractory MM and as part of combination regimens in newly diagnosed patients. Phase III studies in combination with lenalidomide-dexamethasone are ongoing.
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phase 1 study of twice weekly ixazomib an oral Proteasome Inhibitor in relapsed refractory multiple myeloma patients
Blood, 2014Co-Authors: Paul G. Richardson, Jacob P Laubach, Neeraj Gupta, Michael Wang, Andrzej J Jakubowiak, Donald R Harvey, Moshe Talpaz, Deborah Berg, Jiang Yu, Alessandra Di BaccoAbstract:Ixazomib is the first investigational oral Proteasome Inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%,
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Proteasome Inhibitor therapy in multiple myeloma
Molecular Cancer Therapeutics, 2005Co-Authors: Dharminder Chauhan, Constantine S Mitsiades, Paul G. Richardson, Teru Hideshima, Kenneth C AndersonAbstract:Multiple myeloma remains incurable despite available therapies, and novel therapies that target both tumor cell and bone marrow microenvironment are urgently needed. Preclinical in vitro and in vivo studies show remarkable anti-multiple myeloma activity of the Proteasome Inhibitor bortezomib/PS-341 even in multiple myeloma cells refractory to multiple prior therapies, including dexamethasone, melphalan, and thalidomide. Based on these findings, the U.S. Food and Drug Administration recently approved the first Proteasome Inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of relapsed/refractory multiple myeloma. Bortezomib therapy has set an outstanding example of translational research in the field of oncology. Genomics and proteomic studies further provide rationale for combining bortezomib with conventional and novel agents to inhibit multiple myeloma growth, overcome drug resistance, reduce attendant toxicity, and improve patient outcome in multiple myeloma.
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bortezomib ps 341 a novel first in class Proteasome Inhibitor for the treatment of multiple myeloma and other cancers
Cancer Control, 2003Co-Authors: Paul G. Richardson, Teru Hideshima, Kenneth C AndersonAbstract:BackgroundMultiple myeloma (MM) is an incurable malignancy that is diagnosed in approximately 15,000 people in the United States each year. The novel Proteasome Inhibitor bortezomib has shown antit...
