Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model
Summary Our previous study showed that the novel proteasome inhibitor NPI‐0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM‐xenografts demonstrated that NPI‐0052 is well tolerat...
Gespeichert in:
| Veröffentlicht in: | British journal of haematology 2010-05, Vol.149 (4), p.550-559 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 559 |
|---|---|
| container_issue | 4 |
| container_start_page | 550 |
| container_title | British journal of haematology |
| container_volume | 149 |
| creator | Singh, Ajita V. Palladino, Michael A. Lloyd, George Kenneth Potts, Barbara C. Chauhan, Dharminder Anderson, Kenneth C. |
| description | Summary
Our previous study showed that the novel proteasome inhibitor NPI‐0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM‐xenografts demonstrated that NPI‐0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase‐1 clinical trial of NPI‐0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI‐0052 using human MM xenograft murine model. Our results showed that NPI‐0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin‐like (CT‐L, β5), trypsin‐like (T‐L, β2), and caspase‐like (C‐L, β1) activities in extra‐vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs ( |
| doi_str_mv | 10.1111/j.1365-2141.2010.08144.x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4427841</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>745934895</sourcerecordid><originalsourceid>FETCH-LOGICAL-c6014-b3eaaa0d2decd6249815400465daf997a88797061b3cd96c06e7e980eaa58f6b3</originalsourceid><addsrcrecordid>eNqNkc9u1DAQxiMEokvhFZAvCHrYZZw4_w4gQQW0qIIe4GxNnEnXq9je2km74cQDcOAZeRK87LLADV9szfzmm0_-koRxWPB4nq8WPCvyecoFX6QQq1BxIRabO8ns0LibzACgnHMQ1VHyIIQVAM8g5_eToxSyjIs8myXfLpfoDSrXThaNVgxty6jrtEI1sTCMrabAXMeGJTHrbqhna-8GwuAMMW2XutGD8-zD5fmPr98B8pQ9M-j1F2d0cxIBhmw5GrRs3WOIi6bBGWQbsu7KYzcwM3ptiRnXUv8wuddhH-jR_j5OPr998-n0bH7x8d356auLuSqAi3mTESJCm7ak2iIVdcVzASCKvMWurkusqrIuoeBNptq6UFBQSXUFcSqvuqLJjpOXO9312BhqFdnBYy_XXkfrk3So5b8dq5fyyt1IIdKyEjwKPN0LeHc9Uhik0UFR36MlNwZZirzORFXnkax2pPIuBE_dYQsHuc1SruQ2MrmNTG6zlL-ylJs4-vhvl4fB3-FF4MkewKCw7zxapcMfLi3z-DVl5F7suFvd0_TfBuTr92fbV_YTKNu-AA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>745934895</pqid></control><display><type>article</type><title>Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Wiley Free Content</source><creator>Singh, Ajita V. ; Palladino, Michael A. ; Lloyd, George Kenneth ; Potts, Barbara C. ; Chauhan, Dharminder ; Anderson, Kenneth C.</creator><creatorcontrib>Singh, Ajita V. ; Palladino, Michael A. ; Lloyd, George Kenneth ; Potts, Barbara C. ; Chauhan, Dharminder ; Anderson, Kenneth C.</creatorcontrib><description>Summary
Our previous study showed that the novel proteasome inhibitor NPI‐0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM‐xenografts demonstrated that NPI‐0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase‐1 clinical trial of NPI‐0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI‐0052 using human MM xenograft murine model. Our results showed that NPI‐0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin‐like (CT‐L, β5), trypsin‐like (T‐L, β2), and caspase‐like (C‐L, β1) activities in extra‐vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound (3H‐NPI‐0052) in mice demonstrated that NPI‐0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S‐bearing mice with NPI‐0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.</description><identifier>ISSN: 0007-1048</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/j.1365-2141.2010.08144.x</identifier><identifier>PMID: 20331453</identifier><identifier>CODEN: BJHEAL</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; apoptosis ; Biological and medical sciences ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical - methods ; Hematologic and hematopoietic diseases ; Humans ; Immunodeficiencies. Immunoglobulinopathies ; Immunoglobulinopathies ; Immunopathology ; Kidney - metabolism ; Lactones - pharmacokinetics ; Lactones - pharmacology ; Lactones - therapeutic use ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Male ; Medical sciences ; Mice ; multiple myeloma ; pharmacology ; Plasmacytoma - drug therapy ; Plasmacytoma - metabolism ; Plasmacytoma - pathology ; Proteasome Inhibitors ; Pyrroles - pharmacokinetics ; Pyrroles - pharmacology ; Pyrroles - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays</subject><ispartof>British journal of haematology, 2010-05, Vol.149 (4), p.550-559</ispartof><rights>2010 Blackwell Publishing Ltd</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6014-b3eaaa0d2decd6249815400465daf997a88797061b3cd96c06e7e980eaa58f6b3</citedby><cites>FETCH-LOGICAL-c6014-b3eaaa0d2decd6249815400465daf997a88797061b3cd96c06e7e980eaa58f6b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2141.2010.08144.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2141.2010.08144.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27903,27904,45553,45554,46388,46812</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22759817$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20331453$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singh, Ajita V.</creatorcontrib><creatorcontrib>Palladino, Michael A.</creatorcontrib><creatorcontrib>Lloyd, George Kenneth</creatorcontrib><creatorcontrib>Potts, Barbara C.</creatorcontrib><creatorcontrib>Chauhan, Dharminder</creatorcontrib><creatorcontrib>Anderson, Kenneth C.</creatorcontrib><title>Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description>Summary
Our previous study showed that the novel proteasome inhibitor NPI‐0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM‐xenografts demonstrated that NPI‐0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase‐1 clinical trial of NPI‐0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI‐0052 using human MM xenograft murine model. Our results showed that NPI‐0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin‐like (CT‐L, β5), trypsin‐like (T‐L, β2), and caspase‐like (C‐L, β1) activities in extra‐vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound (3H‐NPI‐0052) in mice demonstrated that NPI‐0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S‐bearing mice with NPI‐0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>apoptosis</subject><subject>Biological and medical sciences</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Immunodeficiencies. Immunoglobulinopathies</subject><subject>Immunoglobulinopathies</subject><subject>Immunopathology</subject><subject>Kidney - metabolism</subject><subject>Lactones - pharmacokinetics</subject><subject>Lactones - pharmacology</subject><subject>Lactones - therapeutic use</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>multiple myeloma</subject><subject>pharmacology</subject><subject>Plasmacytoma - drug therapy</subject><subject>Plasmacytoma - metabolism</subject><subject>Plasmacytoma - pathology</subject><subject>Proteasome Inhibitors</subject><subject>Pyrroles - pharmacokinetics</subject><subject>Pyrroles - pharmacology</subject><subject>Pyrroles - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0007-1048</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc9u1DAQxiMEokvhFZAvCHrYZZw4_w4gQQW0qIIe4GxNnEnXq9je2km74cQDcOAZeRK87LLADV9szfzmm0_-koRxWPB4nq8WPCvyecoFX6QQq1BxIRabO8ns0LibzACgnHMQ1VHyIIQVAM8g5_eToxSyjIs8myXfLpfoDSrXThaNVgxty6jrtEI1sTCMrabAXMeGJTHrbqhna-8GwuAMMW2XutGD8-zD5fmPr98B8pQ9M-j1F2d0cxIBhmw5GrRs3WOIi6bBGWQbsu7KYzcwM3ptiRnXUv8wuddhH-jR_j5OPr998-n0bH7x8d356auLuSqAi3mTESJCm7ak2iIVdcVzASCKvMWurkusqrIuoeBNptq6UFBQSXUFcSqvuqLJjpOXO9312BhqFdnBYy_XXkfrk3So5b8dq5fyyt1IIdKyEjwKPN0LeHc9Uhik0UFR36MlNwZZirzORFXnkax2pPIuBE_dYQsHuc1SruQ2MrmNTG6zlL-ylJs4-vhvl4fB3-FF4MkewKCw7zxapcMfLi3z-DVl5F7suFvd0_TfBuTr92fbV_YTKNu-AA</recordid><startdate>201005</startdate><enddate>201005</enddate><creator>Singh, Ajita V.</creator><creator>Palladino, Michael A.</creator><creator>Lloyd, George Kenneth</creator><creator>Potts, Barbara C.</creator><creator>Chauhan, Dharminder</creator><creator>Anderson, Kenneth C.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>201005</creationdate><title>Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model</title><author>Singh, Ajita V. ; Palladino, Michael A. ; Lloyd, George Kenneth ; Potts, Barbara C. ; Chauhan, Dharminder ; Anderson, Kenneth C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6014-b3eaaa0d2decd6249815400465daf997a88797061b3cd96c06e7e980eaa58f6b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>apoptosis</topic><topic>Biological and medical sciences</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Immunodeficiencies. Immunoglobulinopathies</topic><topic>Immunoglobulinopathies</topic><topic>Immunopathology</topic><topic>Kidney - metabolism</topic><topic>Lactones - pharmacokinetics</topic><topic>Lactones - pharmacology</topic><topic>Lactones - therapeutic use</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>multiple myeloma</topic><topic>pharmacology</topic><topic>Plasmacytoma - drug therapy</topic><topic>Plasmacytoma - metabolism</topic><topic>Plasmacytoma - pathology</topic><topic>Proteasome Inhibitors</topic><topic>Pyrroles - pharmacokinetics</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrroles - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Tumor Cells, Cultured</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Ajita V.</creatorcontrib><creatorcontrib>Palladino, Michael A.</creatorcontrib><creatorcontrib>Lloyd, George Kenneth</creatorcontrib><creatorcontrib>Potts, Barbara C.</creatorcontrib><creatorcontrib>Chauhan, Dharminder</creatorcontrib><creatorcontrib>Anderson, Kenneth C.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Ajita V.</au><au>Palladino, Michael A.</au><au>Lloyd, George Kenneth</au><au>Potts, Barbara C.</au><au>Chauhan, Dharminder</au><au>Anderson, Kenneth C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2010-05</date><risdate>2010</risdate><volume>149</volume><issue>4</issue><spage>550</spage><epage>559</epage><pages>550-559</pages><issn>0007-1048</issn><eissn>1365-2141</eissn><coden>BJHEAL</coden><abstract>Summary
Our previous study showed that the novel proteasome inhibitor NPI‐0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM‐xenografts demonstrated that NPI‐0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase‐1 clinical trial of NPI‐0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI‐0052 using human MM xenograft murine model. Our results showed that NPI‐0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin‐like (CT‐L, β5), trypsin‐like (T‐L, β2), and caspase‐like (C‐L, β1) activities in extra‐vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound (3H‐NPI‐0052) in mice demonstrated that NPI‐0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S‐bearing mice with NPI‐0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>20331453</pmid><doi>10.1111/j.1365-2141.2010.08144.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-1048 |
| ispartof | British journal of haematology, 2010-05, Vol.149 (4), p.550-559 |
| issn | 0007-1048 1365-2141 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4427841 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content |
| subjects | Animals Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use apoptosis Biological and medical sciences Dose-Response Relationship, Drug Drug Evaluation, Preclinical - methods Hematologic and hematopoietic diseases Humans Immunodeficiencies. Immunoglobulinopathies Immunoglobulinopathies Immunopathology Kidney - metabolism Lactones - pharmacokinetics Lactones - pharmacology Lactones - therapeutic use Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Mice multiple myeloma pharmacology Plasmacytoma - drug therapy Plasmacytoma - metabolism Plasmacytoma - pathology Proteasome Inhibitors Pyrroles - pharmacokinetics Pyrroles - pharmacology Pyrroles - therapeutic use Rats Rats, Sprague-Dawley Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| title | Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T03%3A43%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pharmacodynamic%20and%20efficacy%20studies%20of%20the%20novel%20proteasome%20inhibitor%20NPI%E2%80%900052%20(marizomib)%20in%20a%20human%20plasmacytoma%20xenograft%20murine%20model&rft.jtitle=British%20journal%20of%20haematology&rft.au=Singh,%20Ajita%20V.&rft.date=2010-05&rft.volume=149&rft.issue=4&rft.spage=550&rft.epage=559&rft.pages=550-559&rft.issn=0007-1048&rft.eissn=1365-2141&rft.coden=BJHEAL&rft_id=info:doi/10.1111/j.1365-2141.2010.08144.x&rft_dat=%3Cproquest_pubme%3E745934895%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=745934895&rft_id=info:pmid/20331453&rfr_iscdi=true |