関: pS341

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/01/02 21:47:08」(JST)

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Bortezomib (BAN, INN and USAN. Originally codenamed PS-341; marketed as Velcade by Millennium Pharmaceuticals and Cytomib by Venus Remedies) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma.^[1]^[2] In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

Origin and development

Bortezomib was originally synthesized in 1995 at Myogenics. The drug (PS-341) was tested in a small Phase I clinical trial on patients with Multiple Myeloma. It was brought to further clinical trials by Millennium Pharmaceuticals in October 1999.

In May 2003, seven years after the initial synthesis, Bortezomib (marketed as Velcade by Millennium Pharmaceuticals Inc.) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.^[3] Bortezomib is approved for initial treatment of patients with Multiple Myeloma by the U.S. FDA in 2008.^[4]

Later in August 2014, this Administration approved Velcade for the retreatment of adult patients with Multiple Myeloma^[5] who had previously responded to Velcade therapy and relapsed at least six months following completion of prior treatment.

Pharmacology

Bortezomib bound to the core particle in a yeast proteasome. The bortezomib molecule is in the center colored by atom type (boron = pink, carbon = cyan, nitrogen = blue, oxygen = red), surrounded by the local protein surface. The blue patch is catalytic threonine residue whose activity is blocked by the presence of bortezomib.

Structure

The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid. Peptides are written N-terminus to C-terminus, and this convention is used here even though the "C-terminus" is a boronic acid instead of a carboxylic acid.

Mechanism

The boron atom in bortezomib binds the catalytic site of the 26S proteasome^[6] with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitylated proteins, and also cleanses the cell of abnormal or misfolded proteins. Clinical and preclinical data support a role in maintaining the immortal phenotype of myeloma cells, and cell-culture and xenograft data support a similar function in solid tumor cancers. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways. Recently, it was found that bortezomib caused a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome.^[7] Some intracellular peptides have been shown to be biologically active, and so the effect of bortezomib on the levels of intracellular peptides may contribute to the biological and/or side effects of the drug.

Pharmacokinetics and pharmacodynamics

Bortezomib is rapidly cleared following intravenous administration.^[8] Peak concentrations are reached at about 30 minutes. Drug levels can no longer be measured after an hour. Pharmacodynamics are measured by measuring proteasome inhibition in peripheral blood mononuclear cells. The much greater sensitivity of myeloma cell lines and mantle cell lines to proteasome inhibition compared with normal peripheral blood mononuclear cells and most other cancer cell lines is poorly understood.

Costs

UK

NICE recommended against Velcade in Oct 2006 due to its cost.^[9]

The company proposed a cost reduction for multiple myeloma,^[10] and this was taken up in the UK.^[11]

Adverse effects

Bortezomib is associated with peripheral neuropathy in 30% of patients; occasionally, it can be painful. This can be worse in patients with pre-existing neuropathy. In addition, myelosuppression causing neutropenia and thrombocytopenia can also occur and be dose-limiting. However, these side effects are usually mild relative to bone marrow transplantation and other treatment options for patients with advanced disease. Bortezomib is associated with a high rate of shingles,^[12] although prophylactic acyclovir can reduce the risk of this.^[13]

Gastro-intestinal (GI) effects and asthenia are the most common adverse events.^[14]

Drug interactions

Green tea extract epigallocatechin gallate (EGCG), which had been expected to have a synergistic effect, was found by Encouse B. Golden, et al. to reduce the effectiveness of bortezomib.^[15]

Therapeutic efficacy

Two open-label, phase II trials (SUMMIT and CREST) established the efficacy of bortezomib 1.3 mg/m² (with or without dexamethasone) administered by intravenous bolus on days 1,4,8, and 11 of a 21-day cycle for a maximum of eight cycles in heavily pretreated patients with relapsed/refractory multiple myeloma.^[16] The phase III APEX trial demonstrated the superiority of bortezomib 1.3 mg/m² over a high-dose dexamethasone regimen (e.g. median TTP 6.2 vs 3.5 months, and 1-year survival 80% vs 66%).^[16]

References

^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
^ House, Douglas W. (2014-10-09). "FDA clears Velcade label expansion". Seeking Alpha.
^ Adams J, Kauffman M (2004). "Development of the Proteasome Inhibitor Velcade (Bortezomib)". Cancer Invest 22 (2): 304–11. doi:10.1081/CNV-120030218. PMID 15199612.
^ "U.S. Department of Health and Human Services". fda.gov. June 23, 2008.
^ "Millenium: The Takeda Oncology Company". .millennium.com. 2014-08-08.
^ Bonvini P, Zorzi E, Basso G, Rosolen A (2007). "Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma". Leukemia 21 (4): 838–42. doi:10.1038/sj.leu.2404528. PMID 17268529.
^ Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD (2013). "Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib". PLoS One 8 (8): e53263. doi:10.1371/journal.pone.0053263. PMC 3538785. PMID 23308178.
^ Voorhees PM, Dees EC, O'Neil B, Orlowski RZ (2003). "The proteasome as a target for cancer therapy". Clin Cancer Res 9 (17): 6316–25. PMID 14695130.
^ "NHS watchdog rejects cancer drug". BBC News UK. 2006-10-20. Retrieved 2009-08-14.
^ "Summary of VELCADE Response Scheme". Retrieved 2009-08-14.
^ "More Velcade-Style Risk-Sharing In The UK?". Euro Pharma Today. 2009-01-21. Retrieved 2009-08-14.
^ Oakervee HE, Popat R, Curry N, et al. (2005). "PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma". Br J Haematol 129 (6): 755–62. doi:10.1111/j.1365-2141.2005.05519.x. PMID 15953001.
^ Pour L., Adam Z., Buresova L., et al. (2009). "Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib". Clinical Lymphoma & Myeloma 9 (2): 151–3. doi:10.3816/CLM.2009.n.036. PMID 19406726.
^ Highlights Of Prescribing Information
^ Golden, EB; Lam, PY; Kardosh, A; Gaffney, KJ; Cadenas, E; Louie, SG; Petasis, NA; Chen, TC; Schönthal, AH (4 June 2009). "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.". Blood 113 (23): 5927–37. doi:10.1182/blood-2008-07-171389. PMID 19190249.
^ ^a ^b Curran M, McKeage K. (2009). "Bortezomib: A Review of its Use in Patients with Multiple Myeloma". Drugs 69 (7): 859–888. doi:10.2165/00003495-200969070-00006. PMID 19441872. doi:10.2165/00003495-200969070-00006.

External links

[1]
Myeloma patients campaigning for access to a life prolonging cancer drug
Millennium Pharmaceuticals website on Velcade
Multiple Myeloma Research Foundation article on Velcade
International Myeloma Foundation article on Velcade
U.S. Food and Drugs Administration on Velcade
Dedicated website for European audience
Presentation at 2006 ASCO of the PINNACLE Study on MCL by Dr. Goy, with video/slides

UpToDate Contents

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1. 多発性骨髄腫の治療プロトコル treatment protocols for multiple myeloma
2. 移植候補患者における症候性多発性骨髄腫に対する初期化学療法 initial chemotherapy for symptomatic multiple myeloma in patients who are candidates for transplantation
3. アミロイド心筋症の治療 treatment of amyloid cardiomyopathy
4. 非移植候補患者における症候性多発性骨髄腫に対する初期化学療法 initial chemotherapy for symptomatic multiple myeloma in patients who are not candidates for transplantation
5. 再発性または難治性多発性骨髄腫の治療 treatment of relapsed or refractory multiple myeloma

English Journal

Reactive nucleolar and Cajal body responses to proteasome inhibition in sensory ganglion neurons.

Palanca A1, Casafont I1, Berciano MT1, Lafarga M2.Author information 1Department of Anatomy and Cell Biology, University of Cantabria-IFIMAV, Santander, Spain; "Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.2Department of Anatomy and Cell Biology, University of Cantabria-IFIMAV, Santander, Spain; "Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain. Electronic address: lafargam@unican.es.AbstractThe dysfunction of the ubiquitin proteasome system has been related to a broad array of neurodegenerative disorders in which the accumulation of misfolded protein aggregates causes proteotoxicity. The ability of proteasome inhibitors to induce cell cycle arrest and apoptosis has emerged as a powerful strategy for cancer therapy. Bortezomib is a proteasome inhibitor used as an antineoplastic drug, although its neurotoxicity frequently causes a severe sensory peripheral neuropathy. In this study we used a rat model of bortezomib treatment to study the nucleolar and Cajal body responses to the proteasome inhibition in sensory ganglion neurons that are major targets of bortezomib-induced neurotoxicity. Treatment with bortezomib induced dose-dependent dissociation of protein synthesis machinery (chromatolysis) and nuclear retention of poly(A) RNA granules resulting in neuronal dysfunction. However, as a compensatory response to the proteotoxic stress, both nucleoli and Cajal bodies exhibited reactive changes. These include an increase in the number and size of nucleoli, strong nucleolar incorporation of the RNA precursor 5'-fluorouridine, and increased expression of both 45S rRNA and genes encoding nucleolar proteins UBF, fibrillarin and B23. Taken together, these findings appear to reflect the activation of the nucleolar transcription in response to proteotoxic stress Furthermore, the number of Cajal bodies, a parameter related to transcriptional activity, increases upon proteasome inhibition. We propose that nucleoli and Cajal bodies are important targets in the signaling pathways that are activated by the proteotoxic stress response to proteasome inhibition. The coordinating activity of these two organelles in the production of snRNA, snoRNA and rRNA may contribute to neuronal survival after proteasome inhibition. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
Biochimica et biophysica acta.Biochim Biophys Acta.2014 Jun;1842(6):848-59. doi: 10.1016/j.bbadis.2013.11.016. Epub 2013 Nov 19.
The dysfunction of the ubiquitin proteasome system has been related to a broad array of neurodegenerative disorders in which the accumulation of misfolded protein aggregates causes proteotoxicity. The ability of proteasome inhibitors to induce cell cycle arrest and apoptosis has emerged as a powerfu
PMID 24269586

The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential vanilloid type-2.

Morelli MB1, Offidani M, Alesiani F, Discepoli G, Liberati S, Olivieri A, Santoni M, Santoni G, Leoni P, Nabissi M.Author information 1Section of Experimental Medicine, School of Pharmacy, University of Camerino, Camerino, Italy.AbstractMultiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the accumulation of a monoclonal PC population in the bone marrow (BM). Cannabidiol (CBD) is a non-psychoactive cannabinoid with antitumoural activities, and the transient receptor potential vanilloid type-2 (TRPV2) channel has been reported as a potential CBD receptor. TRPV2 activation by CBD decreases proliferation and increases susceptibility to drug-induced cell death in human cancer cells. However, no functional role has been ascribed to CBD and TRPV2 in MM. In this study, we identified the presence of heterogeneous CD138+TRPV2+ and CD138+TRPV2- PC populations in MM patients, whereas only the CD138+ TRPV2- population was present in RPMI8226 and U266 MM cell lines. Because bortezomib (BORT) is commonly used in MM treatment, we investigated the effects of CBD and BORT in CD138+TRPV2- MM cells and in MM cell lines transfected with TRPV2 (CD138+TRPV2+). These results showed that CBD by itself or in synergy with BORT strongly inhibited growth, arrested cell cycle progression and induced MM cells death by regulating the ERK, AKT and NF-κB pathways with major effects in TRPV2+ cells. These data provide a rationale for using CBD to increase the activity of proteasome inhibitors in MM.
International journal of cancer. Journal international du cancer.Int J Cancer.2014 Jun 1;134(11):2534-46. doi: 10.1002/ijc.28591. Epub 2013 Dec 2.
Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the accumulation of a monoclonal PC population in the bone marrow (BM). Cannabidiol (CBD) is a non-psychoactive cannabinoid with antitumoural activities, and the transient receptor potential vanilloid type-2 (TRPV2) channel has
PMID 24293211

Sequential treatment of HPV E6 and E7-expressing TC-1 cells with bortezomib and celecoxib promotes apoptosis through p-p38 MAPK-mediated downregulation of cyclin D1 and CDK2.

Kim JE1, Lee JI1, Jin DH2, Lee WJ3, Park GB4, Kim S4, Kim YS4, Wu TC5, Hur DY4, Kim D4.Author information 1Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.2Institute for Innovate Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.3Department of Anatomy, Seoul National University, College of Medicine, Seoul, Republic of Korea.4Department of Anatomy and Laboratory for Cancer Immunotherapy, Inje University, College of Medicine, Busan, Republic of Korea.5Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.AbstractInterruption of the cell cycle is accompanied by changes in several related molecules that result in the activation of apoptosis. The present study was performed to verify the apoptotic effects of sequential treatment with bortezomib and celecoxib in TC-1 cells expressing the human papillomavirus (HPV) E6 and E7 proteins. In TC-1 cells sequentially treated with bortezomib and celecoxib, apoptosis was induced through decreased expression of signal transducer and activator of transcription-3 (STAT3), cyclin D1 and cyclin-dependent kinase (CDK) 2, which are major regulators of the G0/G1 cell cycle checkpoint. In addition, increased levels of p21, CHOP, BiP and p-p38 MAPK were identified in these cells. The treatment-induced apoptosis was effectively inhibited by treatment with SB203580, an inhibitor of p-p38. Moreover, the growth of tumors sequentially treated with bortezomib and celecoxib was retarded compared to the growth of tumors exposed to a single treatment with either bortezomib or celecoxib in vivo. We demonstrated that sequential treatment with bortezomib and celecoxib induced apoptosis via p-p38-mediated G0/G1 cell cycle arrest and endoplasmic reticulum (ER) stress. Sequential treatment with these two drugs could therefore be a useful therapy for cervical cancer.
Oncology reports.Oncol Rep.2014 May;31(5):2429-37. doi: 10.3892/or.2014.3082. Epub 2014 Mar 12.
Interruption of the cell cycle is accompanied by changes in several related molecules that result in the activation of apoptosis. The present study was performed to verify the apoptotic effects of sequential treatment with bortezomib and celecoxib in TC-1 cells expressing the human papillomavirus (H
PMID 24627094

Japanese Journal

がんの最新治療各論(5)多発性骨髄腫

今井陽一
東京女子医科大学雑誌 83(3), 160-167, 2013-06-25
形質細胞由来の造血器腫瘍である多発性骨髄腫は血清・尿中の単クローン性免疫グロブリンの産生を特徴とする。貧血などの造血障害、溶骨病変、腎機能障害、易感染性などの様々な臨床症状を伴いADLの低下を伴う場合がみられる難治・再発性の悪性腫瘍である。治療としては従来の化学療法であるMP (メルファラン・プレドニン)療法では完全寛解を得られることは困難で十分な生存期間を得られなかった。近年になって大量化学療法 …
NAID 110009605129

多発性骨髄腫のこれまでの治療と最近の治療について

高橋正知,TAKAHASHI Masatomo
東京女子医科大学雑誌 83(E2), E476-E484, 2013-03-31
多発性骨髄腫(以下MM)は形質細胞の腫瘍性増殖による疾患で、一時的には治療に反応するものの再発が必須である。サリドマイドがMMに有効であることが明らかとなり、その後ボルテゾミブおよびレナリドマイドが治療に用いられ、これまでの標準治療とされてきたメルファラン、プレドニゾンによるMP療法からMMに対する治療が大きく変わりつつある。これまで予後不良因子としての染色体異常、例えば13番異常を持つMM患者は …
NAID 110009575055

多発性骨髄腫の標準的な寛解導入療法-新薬を含む多剤併用療法の現況-

和田眞紀夫,WADA Makio
東京女子医科大学雑誌 83(E2), E470-E475, 2013-03-31
現在、米国、英国などから、多発性骨髄腫および類縁疾患の包括的な診療ガイドラインが公表されている。共通していることは、それぞれ独自に世界の臨床研究データを収集・分析して、高いエビデンスの得られた事項を中心に「根拠に基づいた治療ガイドライン」を組み立てていることである。具体的には(1)無症候性の骨髄腫にはすぐには治療をしないこと、(2)可能な症例では自家幹細胞移植を行う方がよいことなどがエビデンスレベ …
NAID 110009575054

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Bortezomib
Systematic (IUPAC) name
	[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
Clinical data
Trade names	Velcade
AHFS/Drugs.com	monograph
MedlinePlus	a607007
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	AU: C; US: D;
Legal status	℞ Prescription only;
Routes	Intravenous
Pharmacokinetic data
Protein binding	83%
Metabolism	Hepatic, CYP extensively involved
Half-life	9 to 15 hours
Identifiers
CAS number	179324-69-7
ATC code	L01XX32
PubChem	CID 387447
DrugBank	DB00188
ChemSpider	343402
UNII	69G8BD63PP
ChEMBL	CHEMBL325041
Chemical data
Formula	C19H25BN4O4
Molecular mass	384.237 g/mol
	SMILES O=C(N[C@H](C(=O)N[C@H](B(O)O)CC(C)C)Cc1ccccc1)c2nccnc2;
	InChI InChI=1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1 ; Key:GXJABQQUPOEUTA-RDJZCZTQSA-N ;
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　　[★]

英: bortezomib
商: ベルケイド
関: その他の腫瘍用薬

[1] Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.

[house2014-2] House, Douglas W. (2014-10-09). "FDA clears Velcade label expansion". Seeking Alpha.

[pmid15199612-3] Adams J, Kauffman M (2004). "Development of the Proteasome Inhibitor Velcade (Bortezomib)". Cancer Invest 22 (2): 304–11. doi:10.1081/CNV-120030218. PMID 15199612.

[4] "U.S. Department of Health and Human Services". fda.gov. June 23, 2008.

[5] "Millenium: The Takeda Oncology Company". .millennium.com. 2014-08-08.

[pmid17268529-6] Bonvini P, Zorzi E, Basso G, Rosolen A (2007). "Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma". Leukemia 21 (4): 838–42. doi:10.1038/sj.leu.2404528. PMID 17268529.

[pmid23308178-7] Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD (2013). "Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib". PLoS One 8 (8): e53263. doi:10.1371/journal.pone.0053263. PMC 3538785. PMID 23308178.

[8] Voorhees PM, Dees EC, O'Neil B, Orlowski RZ (2003). "The proteasome as a target for cancer therapy". Clin Cancer Res 9 (17): 6316–25. PMID 14695130.

[9] "NHS watchdog rejects cancer drug". BBC News UK. 2006-10-20. Retrieved 2009-08-14.

[10] "Summary of VELCADE Response Scheme". Retrieved 2009-08-14.

[11] "More Velcade-Style Risk-Sharing In The UK?". Euro Pharma Today. 2009-01-21. Retrieved 2009-08-14.

[pmid15953001-12] Oakervee HE, Popat R, Curry N, et al. (2005). "PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma". Br J Haematol 129 (6): 755–62. doi:10.1111/j.1365-2141.2005.05519.x. PMID 15953001.

[pmid19406726-13] Pour L., Adam Z., Buresova L., et al. (2009). "Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib". Clinical Lymphoma & Myeloma 9 (2): 151–3. doi:10.3816/CLM.2009.n.036. PMID 19406726.

[14] Highlights Of Prescribing Information

[15] Golden, EB; Lam, PY; Kardosh, A; Gaffney, KJ; Cadenas, E; Louie, SG; Petasis, NA; Chen, TC; Schönthal, AH (4 June 2009). "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.". Blood 113 (23): 5927–37. doi:10.1182/blood-2008-07-171389. PMID 19190249.

[Curran2009-16] Curran M, McKeage K. (2009). "Bortezomib: A Review of its Use in Patients with Multiple Myeloma". Drugs 69 (7): 859–888. doi:10.2165/00003495-200969070-00006. PMID 19441872. doi:10.2165/00003495-200969070-00006.

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bortezomib