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Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program
Background Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. Procedures Eribulin was tested against the PPTP in...
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| Published in: | Pediatric blood & cancer 2013-08, Vol.60 (8), p.1325-1332 |
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| container_end_page | 1332 |
| container_issue | 8 |
| container_start_page | 1325 |
| container_title | Pediatric blood & cancer |
| container_volume | 60 |
| creator | Kolb, E. Anders Gorlick, Richard Reynolds, C. Patrick Kang, Min H. Carol, Hernan Lock, Richard Keir, Stephen T. Maris, John M. Billups, Catherine A. DesJardins, Christopher Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. |
| description | Background
Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.
Procedures
Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.
Results
In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range |
| doi_str_mv | 10.1002/pbc.24517 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4263960</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2994989091</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5477-b00f6020e20205dc693730ce6991103dbecdd8a3b820f956ae48fc9509e0f2863</originalsourceid><addsrcrecordid>eNp10c9v0zAUB3ALgdgYHPgHkCUum7Rs_hHb8QUJCnSTqrIDiKPlOC-dR-oEOxn0v8drt2ogcbEt--Ov3tND6DUlZ5QQdj7U7oyVgqon6JCKUhSCUPV0fyb6AL1I6SZTSUT1HB0wLgTXVB2ieBn86G2HR0ijDyt8nEa7AkxPcN9iiL6eOh9OscWhv4XMpu0Frn1o7ni2YTzF9QaP14AHaLwdo3d4iOCy8-5R9BD7VbTrl-hZa7sEr-73I_Tt86evs4ti8WV-OXu_KJwolSpqQlpJGAGWF9E4qbnixIHUmlLCmxpc01SW1xUjrRbSQlm1TguigbSskvwIvdvlDlO9hsblQqPtzBD92saN6a03f78Ef21W_a0pmeRakhxwfB8Q-59TbsKsfXLQdTZAPyVDuVRVVTLGM337D73ppxhye1tFCS0rldXJTrnYpxSh3RdDibmbpMmTNNtJZvvmcfV7-TC6DM534JfvYPP_JHP1YfYQWex--DTC7_0PG38YqbgS5vtybvTV4qO4WC7NnP8BB2G3NA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1367101487</pqid></control><display><type>article</type><title>Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program</title><source>Wiley</source><creator>Kolb, E. Anders ; Gorlick, Richard ; Reynolds, C. Patrick ; Kang, Min H. ; Carol, Hernan ; Lock, Richard ; Keir, Stephen T. ; Maris, John M. ; Billups, Catherine A. ; DesJardins, Christopher ; Kurmasheva, Raushan T. ; Houghton, Peter J. ; Smith, Malcolm A.</creator><creatorcontrib>Kolb, E. Anders ; Gorlick, Richard ; Reynolds, C. Patrick ; Kang, Min H. ; Carol, Hernan ; Lock, Richard ; Keir, Stephen T. ; Maris, John M. ; Billups, Catherine A. ; DesJardins, Christopher ; Kurmasheva, Raushan T. ; Houghton, Peter J. ; Smith, Malcolm A.</creatorcontrib><description>Background
Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.
Procedures
Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.
Results
In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1–14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event‐free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR.
Conclusions
The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer 2013;601325‐1332. © 2013 Wiley Periodicals, Inc.</description><identifier>ISSN: 1545-5009</identifier><identifier>EISSN: 1545-5017</identifier><identifier>DOI: 10.1002/pbc.24517</identifier><identifier>PMID: 23553917</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Animals ; Cell Line, Tumor ; developmental therapeutics ; Furans - pharmacology ; Hematology ; Humans ; Ketones - pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mice, SCID ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - pathology ; Oncology ; Pediatrics ; PI3K inhibitor ; preclinical testing ; Tubulin Modulators - pharmacology ; Xenograft Model Antitumor Assays - methods</subject><ispartof>Pediatric blood & cancer, 2013-08, Vol.60 (8), p.1325-1332</ispartof><rights>Copyright © 2013 Wiley Periodicals, Inc.</rights><rights>2013 Wiley Periodicals, Inc. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5477-b00f6020e20205dc693730ce6991103dbecdd8a3b820f956ae48fc9509e0f2863</citedby><cites>FETCH-LOGICAL-c5477-b00f6020e20205dc693730ce6991103dbecdd8a3b820f956ae48fc9509e0f2863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23553917$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kolb, E. Anders</creatorcontrib><creatorcontrib>Gorlick, Richard</creatorcontrib><creatorcontrib>Reynolds, C. Patrick</creatorcontrib><creatorcontrib>Kang, Min H.</creatorcontrib><creatorcontrib>Carol, Hernan</creatorcontrib><creatorcontrib>Lock, Richard</creatorcontrib><creatorcontrib>Keir, Stephen T.</creatorcontrib><creatorcontrib>Maris, John M.</creatorcontrib><creatorcontrib>Billups, Catherine A.</creatorcontrib><creatorcontrib>DesJardins, Christopher</creatorcontrib><creatorcontrib>Kurmasheva, Raushan T.</creatorcontrib><creatorcontrib>Houghton, Peter J.</creatorcontrib><creatorcontrib>Smith, Malcolm A.</creatorcontrib><title>Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program</title><title>Pediatric blood & cancer</title><addtitle>Pediatr Blood Cancer</addtitle><description>Background
Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.
Procedures
Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.
Results
In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1–14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event‐free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR.
Conclusions
The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer 2013;601325‐1332. © 2013 Wiley Periodicals, Inc.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>developmental therapeutics</subject><subject>Furans - pharmacology</subject><subject>Hematology</subject><subject>Humans</subject><subject>Ketones - pharmacology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Mice, SCID</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Oncology</subject><subject>Pediatrics</subject><subject>PI3K inhibitor</subject><subject>preclinical testing</subject><subject>Tubulin Modulators - pharmacology</subject><subject>Xenograft Model Antitumor Assays - methods</subject><issn>1545-5009</issn><issn>1545-5017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp10c9v0zAUB3ALgdgYHPgHkCUum7Rs_hHb8QUJCnSTqrIDiKPlOC-dR-oEOxn0v8drt2ogcbEt--Ov3tND6DUlZ5QQdj7U7oyVgqon6JCKUhSCUPV0fyb6AL1I6SZTSUT1HB0wLgTXVB2ieBn86G2HR0ijDyt8nEa7AkxPcN9iiL6eOh9OscWhv4XMpu0Frn1o7ni2YTzF9QaP14AHaLwdo3d4iOCy8-5R9BD7VbTrl-hZa7sEr-73I_Tt86evs4ti8WV-OXu_KJwolSpqQlpJGAGWF9E4qbnixIHUmlLCmxpc01SW1xUjrRbSQlm1TguigbSskvwIvdvlDlO9hsblQqPtzBD92saN6a03f78Ef21W_a0pmeRakhxwfB8Q-59TbsKsfXLQdTZAPyVDuVRVVTLGM337D73ppxhye1tFCS0rldXJTrnYpxSh3RdDibmbpMmTNNtJZvvmcfV7-TC6DM534JfvYPP_JHP1YfYQWex--DTC7_0PG38YqbgS5vtybvTV4qO4WC7NnP8BB2G3NA</recordid><startdate>201308</startdate><enddate>201308</enddate><creator>Kolb, E. Anders</creator><creator>Gorlick, Richard</creator><creator>Reynolds, C. Patrick</creator><creator>Kang, Min H.</creator><creator>Carol, Hernan</creator><creator>Lock, Richard</creator><creator>Keir, Stephen T.</creator><creator>Maris, John M.</creator><creator>Billups, Catherine A.</creator><creator>DesJardins, Christopher</creator><creator>Kurmasheva, Raushan T.</creator><creator>Houghton, Peter J.</creator><creator>Smith, Malcolm A.</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7TK</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201308</creationdate><title>Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program</title><author>Kolb, E. Anders ; Gorlick, Richard ; Reynolds, C. Patrick ; Kang, Min H. ; Carol, Hernan ; Lock, Richard ; Keir, Stephen T. ; Maris, John M. ; Billups, Catherine A. ; DesJardins, Christopher ; Kurmasheva, Raushan T. ; Houghton, Peter J. ; Smith, Malcolm A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5477-b00f6020e20205dc693730ce6991103dbecdd8a3b820f956ae48fc9509e0f2863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>developmental therapeutics</topic><topic>Furans - pharmacology</topic><topic>Hematology</topic><topic>Humans</topic><topic>Ketones - pharmacology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Mice, SCID</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Oncology</topic><topic>Pediatrics</topic><topic>PI3K inhibitor</topic><topic>preclinical testing</topic><topic>Tubulin Modulators - pharmacology</topic><topic>Xenograft Model Antitumor Assays - methods</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kolb, E. Anders</creatorcontrib><creatorcontrib>Gorlick, Richard</creatorcontrib><creatorcontrib>Reynolds, C. Patrick</creatorcontrib><creatorcontrib>Kang, Min H.</creatorcontrib><creatorcontrib>Carol, Hernan</creatorcontrib><creatorcontrib>Lock, Richard</creatorcontrib><creatorcontrib>Keir, Stephen T.</creatorcontrib><creatorcontrib>Maris, John M.</creatorcontrib><creatorcontrib>Billups, Catherine A.</creatorcontrib><creatorcontrib>DesJardins, Christopher</creatorcontrib><creatorcontrib>Kurmasheva, Raushan T.</creatorcontrib><creatorcontrib>Houghton, Peter J.</creatorcontrib><creatorcontrib>Smith, Malcolm A.</creatorcontrib><collection>Istex</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>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Pediatric blood & cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kolb, E. Anders</au><au>Gorlick, Richard</au><au>Reynolds, C. Patrick</au><au>Kang, Min H.</au><au>Carol, Hernan</au><au>Lock, Richard</au><au>Keir, Stephen T.</au><au>Maris, John M.</au><au>Billups, Catherine A.</au><au>DesJardins, Christopher</au><au>Kurmasheva, Raushan T.</au><au>Houghton, Peter J.</au><au>Smith, Malcolm A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program</atitle><jtitle>Pediatric blood & cancer</jtitle><addtitle>Pediatr Blood Cancer</addtitle><date>2013-08</date><risdate>2013</risdate><volume>60</volume><issue>8</issue><spage>1325</spage><epage>1332</epage><pages>1325-1332</pages><issn>1545-5009</issn><eissn>1545-5017</eissn><abstract>Background
Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.
Procedures
Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.
Results
In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1–14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event‐free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR.
Conclusions
The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer 2013;601325‐1332. © 2013 Wiley Periodicals, Inc.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>23553917</pmid><doi>10.1002/pbc.24517</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | Wiley |
| subjects | Animals Cell Line, Tumor developmental therapeutics Furans - pharmacology Hematology Humans Ketones - pharmacology Mice Mice, Inbred BALB C Mice, Nude Mice, SCID Neoplasms, Experimental - drug therapy Neoplasms, Experimental - pathology Oncology Pediatrics PI3K inhibitor preclinical testing Tubulin Modulators - pharmacology Xenograft Model Antitumor Assays - methods |
| title | Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program |
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