Quantifying the CDK inhibitor VMY-1-103's activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI
The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Usin...
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| Veröffentlicht in: | Cell cycle (Georgetown, Tex.) Tex.), 2012-10, Vol.11 (20), p.3801-3809 |
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| creator | Sirajuddin, Paul Das, Sudeep Ringer, Lymor Rodriguez, Olga C. Sivakumar, Angiela Lee, Yi-Chien Uren, Aykut Fricke, Stanley T. Rood, Brian Ozcan, Alpay Wang, Sean S. Karam, Sana Yenugonda, Venkata Salinas, Patricia Petricoin III, Emanuel Pishvaian, Michael Lisanti, Michael P. Wang, Yue Schlegel, Richard Moasser, Bahram Albanese, Chris |
| description | The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma. |
| doi_str_mv | 10.4161/cc.21988 |
| format | Article |
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Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma.</description><identifier>ISSN: 1538-4101</identifier><identifier>EISSN: 1551-4005</identifier><identifier>DOI: 10.4161/cc.21988</identifier><identifier>PMID: 22983062</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Adenine - analogs & derivatives ; Adenine - chemistry ; Adenine - pharmacokinetics ; Adenine - pharmacology ; animal models ; Animals ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Binding ; Biological Availability ; Biology ; Bioscience ; Calcium ; Cancer ; CDK inhibitor ; Cell ; Cell Cycle - drug effects ; Cerebellar Neoplasms - drug therapy ; Cerebellar Neoplasms - genetics ; Cerebellar Neoplasms - metabolism ; Chromatography, Liquid ; Cycle ; Cyclin-Dependent Kinases - antagonists & inhibitors ; Cyclin-Dependent Kinases - genetics ; Cyclin-Dependent Kinases - metabolism ; Dansyl Compounds - pharmacokinetics ; Dansyl Compounds - pharmacology ; Humans ; Landes ; Magnetic Resonance Imaging ; medulloblastoma ; Medulloblastoma - drug therapy ; Medulloblastoma - genetics ; Medulloblastoma - metabolism ; Mice ; MR-spectroscopy ; MRI ; Organogenesis ; prostate ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Tandem Mass Spectrometry</subject><ispartof>Cell cycle (Georgetown, Tex.), 2012-10, Vol.11 (20), p.3801-3809</ispartof><rights>Copyright © 2012 Landes Bioscience 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-aeaaf03ab293fcb0a911314bc817ce1577c4c2a051a2656adac0e960c86151dc3</citedby><cites>FETCH-LOGICAL-c497t-aeaaf03ab293fcb0a911314bc817ce1577c4c2a051a2656adac0e960c86151dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495823/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495823/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22983062$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sirajuddin, Paul</creatorcontrib><creatorcontrib>Das, Sudeep</creatorcontrib><creatorcontrib>Ringer, Lymor</creatorcontrib><creatorcontrib>Rodriguez, Olga C.</creatorcontrib><creatorcontrib>Sivakumar, Angiela</creatorcontrib><creatorcontrib>Lee, Yi-Chien</creatorcontrib><creatorcontrib>Uren, Aykut</creatorcontrib><creatorcontrib>Fricke, Stanley T.</creatorcontrib><creatorcontrib>Rood, Brian</creatorcontrib><creatorcontrib>Ozcan, Alpay</creatorcontrib><creatorcontrib>Wang, Sean S.</creatorcontrib><creatorcontrib>Karam, Sana</creatorcontrib><creatorcontrib>Yenugonda, Venkata</creatorcontrib><creatorcontrib>Salinas, Patricia</creatorcontrib><creatorcontrib>Petricoin III, Emanuel</creatorcontrib><creatorcontrib>Pishvaian, Michael</creatorcontrib><creatorcontrib>Lisanti, Michael P.</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Schlegel, Richard</creatorcontrib><creatorcontrib>Moasser, Bahram</creatorcontrib><creatorcontrib>Albanese, Chris</creatorcontrib><title>Quantifying the CDK inhibitor VMY-1-103's activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI</title><title>Cell cycle (Georgetown, Tex.)</title><addtitle>Cell Cycle</addtitle><description>The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma.</description><subject>Adenine - analogs & derivatives</subject><subject>Adenine - chemistry</subject><subject>Adenine - pharmacokinetics</subject><subject>Adenine - pharmacology</subject><subject>animal models</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Binding</subject><subject>Biological Availability</subject><subject>Biology</subject><subject>Bioscience</subject><subject>Calcium</subject><subject>Cancer</subject><subject>CDK inhibitor</subject><subject>Cell</subject><subject>Cell Cycle - drug effects</subject><subject>Cerebellar Neoplasms - drug therapy</subject><subject>Cerebellar Neoplasms - genetics</subject><subject>Cerebellar Neoplasms - metabolism</subject><subject>Chromatography, Liquid</subject><subject>Cycle</subject><subject>Cyclin-Dependent Kinases - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinases - genetics</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Dansyl Compounds - pharmacokinetics</subject><subject>Dansyl Compounds - pharmacology</subject><subject>Humans</subject><subject>Landes</subject><subject>Magnetic Resonance Imaging</subject><subject>medulloblastoma</subject><subject>Medulloblastoma - drug therapy</subject><subject>Medulloblastoma - genetics</subject><subject>Medulloblastoma - metabolism</subject><subject>Mice</subject><subject>MR-spectroscopy</subject><subject>MRI</subject><subject>Organogenesis</subject><subject>prostate</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proteins</subject><subject>Tandem Mass Spectrometry</subject><issn>1538-4101</issn><issn>1551-4005</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><recordid>eNqFkF2L1DAUhoso7roK_gLJnd50Jyfp540g9WtxBnFXBa_C6Wm6E-k0Q5JW-u_N7OigeOFNPp_nTXiT5CnwywwKWBFdCqir6l5yDnkOacZ5fv-wllWaAYez5JH33zkXVVnDw-RMiLqSvBDnyfRpwjGYfjHjLQtbzZrXH5gZt6Y1wTr2dfMthRS4fO4ZUjCzCQvDsWPBeD9pNuhZDz4K8fAwzma2LEy7qO5spwfWLmzdpJub1ebmzov7zfXV4-RBj4PXT37NF8mXt28-N-_T9cd3V82rdUpZXYYUNWLPJbailj21HGsACVlLFZSkIS9LykggzwFFkRfYIXFdF5yqAnLoSF4kL4-5-6nd6Y70GBwOau_MDt2iLBr1981oturWzkpmdV4JGQNeHAPIWe-d7k8ucHWoXhGpu-oj-uzPt07g764jwI_AEIvQvjXWk9Ej6RMas9AFQ4M-Za7-owgOomkyKbJrte_6aMijYcbeuh3-sG7oVMBlsK53OJLxSv7z95-Jv7JC</recordid><startdate>20121015</startdate><enddate>20121015</enddate><creator>Sirajuddin, Paul</creator><creator>Das, Sudeep</creator><creator>Ringer, Lymor</creator><creator>Rodriguez, Olga C.</creator><creator>Sivakumar, Angiela</creator><creator>Lee, Yi-Chien</creator><creator>Uren, Aykut</creator><creator>Fricke, Stanley T.</creator><creator>Rood, Brian</creator><creator>Ozcan, Alpay</creator><creator>Wang, Sean S.</creator><creator>Karam, Sana</creator><creator>Yenugonda, Venkata</creator><creator>Salinas, Patricia</creator><creator>Petricoin III, Emanuel</creator><creator>Pishvaian, Michael</creator><creator>Lisanti, Michael P.</creator><creator>Wang, Yue</creator><creator>Schlegel, Richard</creator><creator>Moasser, Bahram</creator><creator>Albanese, Chris</creator><general>Taylor & Francis</general><general>Landes Bioscience</general><scope>0YH</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>5PM</scope></search><sort><creationdate>20121015</creationdate><title>Quantifying the CDK inhibitor VMY-1-103's activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI</title><author>Sirajuddin, Paul ; Das, Sudeep ; Ringer, Lymor ; Rodriguez, Olga C. ; Sivakumar, Angiela ; Lee, Yi-Chien ; Uren, Aykut ; Fricke, Stanley T. ; Rood, Brian ; Ozcan, Alpay ; Wang, Sean S. ; Karam, Sana ; Yenugonda, Venkata ; Salinas, Patricia ; Petricoin III, Emanuel ; Pishvaian, Michael ; Lisanti, Michael P. ; Wang, Yue ; Schlegel, Richard ; Moasser, Bahram ; Albanese, Chris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-aeaaf03ab293fcb0a911314bc817ce1577c4c2a051a2656adac0e960c86151dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adenine - chemistry</topic><topic>Adenine - pharmacokinetics</topic><topic>Adenine - pharmacology</topic><topic>animal models</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Binding</topic><topic>Biological Availability</topic><topic>Biology</topic><topic>Bioscience</topic><topic>Calcium</topic><topic>Cancer</topic><topic>CDK inhibitor</topic><topic>Cell</topic><topic>Cell Cycle - drug effects</topic><topic>Cerebellar Neoplasms - drug therapy</topic><topic>Cerebellar Neoplasms - genetics</topic><topic>Cerebellar Neoplasms - metabolism</topic><topic>Chromatography, Liquid</topic><topic>Cycle</topic><topic>Cyclin-Dependent Kinases - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinases - genetics</topic><topic>Cyclin-Dependent Kinases - metabolism</topic><topic>Dansyl Compounds - pharmacokinetics</topic><topic>Dansyl Compounds - pharmacology</topic><topic>Humans</topic><topic>Landes</topic><topic>Magnetic Resonance Imaging</topic><topic>medulloblastoma</topic><topic>Medulloblastoma - drug therapy</topic><topic>Medulloblastoma - genetics</topic><topic>Medulloblastoma - metabolism</topic><topic>Mice</topic><topic>MR-spectroscopy</topic><topic>MRI</topic><topic>Organogenesis</topic><topic>prostate</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proteins</topic><topic>Tandem Mass Spectrometry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sirajuddin, Paul</creatorcontrib><creatorcontrib>Das, Sudeep</creatorcontrib><creatorcontrib>Ringer, Lymor</creatorcontrib><creatorcontrib>Rodriguez, Olga C.</creatorcontrib><creatorcontrib>Sivakumar, Angiela</creatorcontrib><creatorcontrib>Lee, Yi-Chien</creatorcontrib><creatorcontrib>Uren, Aykut</creatorcontrib><creatorcontrib>Fricke, Stanley T.</creatorcontrib><creatorcontrib>Rood, Brian</creatorcontrib><creatorcontrib>Ozcan, Alpay</creatorcontrib><creatorcontrib>Wang, Sean S.</creatorcontrib><creatorcontrib>Karam, Sana</creatorcontrib><creatorcontrib>Yenugonda, Venkata</creatorcontrib><creatorcontrib>Salinas, Patricia</creatorcontrib><creatorcontrib>Petricoin III, Emanuel</creatorcontrib><creatorcontrib>Pishvaian, Michael</creatorcontrib><creatorcontrib>Lisanti, Michael P.</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Schlegel, Richard</creatorcontrib><creatorcontrib>Moasser, Bahram</creatorcontrib><creatorcontrib>Albanese, Chris</creatorcontrib><collection>Taylor & Francis Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell cycle (Georgetown, Tex.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sirajuddin, Paul</au><au>Das, Sudeep</au><au>Ringer, Lymor</au><au>Rodriguez, Olga C.</au><au>Sivakumar, Angiela</au><au>Lee, Yi-Chien</au><au>Uren, Aykut</au><au>Fricke, Stanley T.</au><au>Rood, Brian</au><au>Ozcan, Alpay</au><au>Wang, Sean S.</au><au>Karam, Sana</au><au>Yenugonda, Venkata</au><au>Salinas, Patricia</au><au>Petricoin III, Emanuel</au><au>Pishvaian, Michael</au><au>Lisanti, Michael P.</au><au>Wang, Yue</au><au>Schlegel, Richard</au><au>Moasser, Bahram</au><au>Albanese, Chris</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Quantifying the CDK inhibitor VMY-1-103's activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI</atitle><jtitle>Cell cycle (Georgetown, Tex.)</jtitle><addtitle>Cell Cycle</addtitle><date>2012-10-15</date><risdate>2012</risdate><volume>11</volume><issue>20</issue><spage>3801</spage><epage>3809</epage><pages>3801-3809</pages><issn>1538-4101</issn><eissn>1551-4005</eissn><abstract>The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>22983062</pmid><doi>10.4161/cc.21988</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1538-4101 |
| ispartof | Cell cycle (Georgetown, Tex.), 2012-10, Vol.11 (20), p.3801-3809 |
| issn | 1538-4101 1551-4005 |
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| recordid | cdi_pubmed_primary_22983062 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Adenine - analogs & derivatives Adenine - chemistry Adenine - pharmacokinetics Adenine - pharmacology animal models Animals Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Binding Biological Availability Biology Bioscience Calcium Cancer CDK inhibitor Cell Cell Cycle - drug effects Cerebellar Neoplasms - drug therapy Cerebellar Neoplasms - genetics Cerebellar Neoplasms - metabolism Chromatography, Liquid Cycle Cyclin-Dependent Kinases - antagonists & inhibitors Cyclin-Dependent Kinases - genetics Cyclin-Dependent Kinases - metabolism Dansyl Compounds - pharmacokinetics Dansyl Compounds - pharmacology Humans Landes Magnetic Resonance Imaging medulloblastoma Medulloblastoma - drug therapy Medulloblastoma - genetics Medulloblastoma - metabolism Mice MR-spectroscopy MRI Organogenesis prostate Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Proteins Tandem Mass Spectrometry |
| title | Quantifying the CDK inhibitor VMY-1-103's activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI |
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