Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101
Histone acetylation has a central role in the control of gene expression, influencing transcriptional control of many genes, including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits histone deacetylase activity in HeLa cell extracts...
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| Veröffentlicht in: | Molecular cancer therapeutics 2003-08, Vol.2 (8), p.721 |
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| creator | Plumb, Jane A Finn, Paul W Williams, Robert J Bandara, Morwenna J Romero, M Rosario Watkins, Claire J La Thangue, Nicholas B Brown, Robert |
| description | Histone acetylation has a central role in the control of gene expression, influencing transcriptional control of many genes,
including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits
histone deacetylase activity in HeLa cell extracts with an IC 50 of 27 n m and induces a concentration-dependent (0.2–5 μ m ) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC 50 s in the range 0.2–3.4 μ m as determined by a clonogenic assay and induces apoptosis. Treatment of nude mice bearing human ovarian and colon tumor xenografts
with PXD101 (10–40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs
of toxicity to the mice. Growth delay is also observed for xenografts of cisplatin-resistant ovarian tumor cells. A marked
increase in acetylation of H4 is detected in blood and tumor of mice 3 h after treatment with PXD101. The inhibition of growth
of human tumor xenografts in mice, with no apparent toxicity, suggests that PXD101 has potential as a novel antitumor agent.
Furthermore, the ability to measure histone acetylation in blood samples could provide a suitable pharmacodynamic end point
to monitor drug activity. |
| format | Article |
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including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits
histone deacetylase activity in HeLa cell extracts with an IC 50 of 27 n m and induces a concentration-dependent (0.2–5 μ m ) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC 50 s in the range 0.2–3.4 μ m as determined by a clonogenic assay and induces apoptosis. Treatment of nude mice bearing human ovarian and colon tumor xenografts
with PXD101 (10–40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs
of toxicity to the mice. Growth delay is also observed for xenografts of cisplatin-resistant ovarian tumor cells. A marked
increase in acetylation of H4 is detected in blood and tumor of mice 3 h after treatment with PXD101. The inhibition of growth
of human tumor xenografts in mice, with no apparent toxicity, suggests that PXD101 has potential as a novel antitumor agent.
Furthermore, the ability to measure histone acetylation in blood samples could provide a suitable pharmacodynamic end point
to monitor drug activity.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>PMID: 12939461</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Acetylation - drug effects ; Animals ; Apoptosis ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - pharmacology ; HeLa Cells ; Histone Deacetylase Inhibitors ; Histone Deacetylases - metabolism ; Histones - metabolism ; Humans ; Hydroxamic Acids ; Mice ; Mice, Nude ; Neoplasms, Experimental - drug therapy ; Structure-Activity Relationship ; Sulfonamides ; Transplantation, Heterologous ; Xenograft Model Antitumor Assays</subject><ispartof>Molecular cancer therapeutics, 2003-08, Vol.2 (8), p.721</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12939461$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Plumb, Jane A</creatorcontrib><creatorcontrib>Finn, Paul W</creatorcontrib><creatorcontrib>Williams, Robert J</creatorcontrib><creatorcontrib>Bandara, Morwenna J</creatorcontrib><creatorcontrib>Romero, M Rosario</creatorcontrib><creatorcontrib>Watkins, Claire J</creatorcontrib><creatorcontrib>La Thangue, Nicholas B</creatorcontrib><creatorcontrib>Brown, Robert</creatorcontrib><title>Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Histone acetylation has a central role in the control of gene expression, influencing transcriptional control of many genes,
including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits
histone deacetylase activity in HeLa cell extracts with an IC 50 of 27 n m and induces a concentration-dependent (0.2–5 μ m ) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC 50 s in the range 0.2–3.4 μ m as determined by a clonogenic assay and induces apoptosis. Treatment of nude mice bearing human ovarian and colon tumor xenografts
with PXD101 (10–40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs
of toxicity to the mice. Growth delay is also observed for xenografts of cisplatin-resistant ovarian tumor cells. A marked
increase in acetylation of H4 is detected in blood and tumor of mice 3 h after treatment with PXD101. The inhibition of growth
of human tumor xenografts in mice, with no apparent toxicity, suggests that PXD101 has potential as a novel antitumor agent.
Furthermore, the ability to measure histone acetylation in blood samples could provide a suitable pharmacodynamic end point
to monitor drug activity.</description><subject>Acetylation - drug effects</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell Line, Tumor</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HeLa Cells</subject><subject>Histone Deacetylase Inhibitors</subject><subject>Histone Deacetylases - metabolism</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Hydroxamic Acids</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides</subject><subject>Transplantation, Heterologous</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kE9PwjAchhejEUS_gunJ25L1z9r1aECBhCgxmHBbuu43WsNa0g7JDnx3UfD0Pof3fQ7vVTLEOS3SIsfs-o_zVGBOB8ldjF9ZhgtJ8G0ywERSyTgeJselUaFV2te9U63V6APizrsISLkazZ2xle2sd8g3aBr8oTO_NNu3yqHVvvUBrcH5TVBNF1HVo84AevPfsEUzGzvvAE1Aaej6rTo5L77Tarme4AzfJzeN2kZ4uOQo-Xx9WY1n6eJ9Oh8_L1JDaNGlwBgRjaRZhTFrBAGmVQWibmoQgueQCc0k5xJ4VleYM0YpL3JGlAApNSZ0lDyevbt91UJd7oJtVejL_x9OhadzwdiNOdgApVZOQwgQQQVtSlIWpSCY_gDs-mjJ</recordid><startdate>20030801</startdate><enddate>20030801</enddate><creator>Plumb, Jane A</creator><creator>Finn, Paul W</creator><creator>Williams, Robert J</creator><creator>Bandara, Morwenna J</creator><creator>Romero, M Rosario</creator><creator>Watkins, Claire J</creator><creator>La Thangue, Nicholas B</creator><creator>Brown, Robert</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20030801</creationdate><title>Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101</title><author>Plumb, Jane A ; Finn, Paul W ; Williams, Robert J ; Bandara, Morwenna J ; Romero, M Rosario ; Watkins, Claire J ; La Thangue, Nicholas B ; Brown, Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h238t-e4427f930b114f72e4cabe7dfde7765e07c49669e60db16443368542a7e99c123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Acetylation - drug effects</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Cell Line, Tumor</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>HeLa Cells</topic><topic>Histone Deacetylase Inhibitors</topic><topic>Histone Deacetylases - metabolism</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Hydroxamic Acids</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides</topic><topic>Transplantation, Heterologous</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Plumb, Jane A</creatorcontrib><creatorcontrib>Finn, Paul W</creatorcontrib><creatorcontrib>Williams, Robert J</creatorcontrib><creatorcontrib>Bandara, Morwenna J</creatorcontrib><creatorcontrib>Romero, M Rosario</creatorcontrib><creatorcontrib>Watkins, Claire J</creatorcontrib><creatorcontrib>La Thangue, Nicholas B</creatorcontrib><creatorcontrib>Brown, Robert</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Plumb, Jane A</au><au>Finn, Paul W</au><au>Williams, Robert J</au><au>Bandara, Morwenna J</au><au>Romero, M Rosario</au><au>Watkins, Claire J</au><au>La Thangue, Nicholas B</au><au>Brown, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2003-08-01</date><risdate>2003</risdate><volume>2</volume><issue>8</issue><spage>721</spage><pages>721-</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Histone acetylation has a central role in the control of gene expression, influencing transcriptional control of many genes,
including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits
histone deacetylase activity in HeLa cell extracts with an IC 50 of 27 n m and induces a concentration-dependent (0.2–5 μ m ) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC 50 s in the range 0.2–3.4 μ m as determined by a clonogenic assay and induces apoptosis. Treatment of nude mice bearing human ovarian and colon tumor xenografts
with PXD101 (10–40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs
of toxicity to the mice. Growth delay is also observed for xenografts of cisplatin-resistant ovarian tumor cells. A marked
increase in acetylation of H4 is detected in blood and tumor of mice 3 h after treatment with PXD101. The inhibition of growth
of human tumor xenografts in mice, with no apparent toxicity, suggests that PXD101 has potential as a novel antitumor agent.
Furthermore, the ability to measure histone acetylation in blood samples could provide a suitable pharmacodynamic end point
to monitor drug activity.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>12939461</pmid></addata></record> |
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| ispartof | Molecular cancer therapeutics, 2003-08, Vol.2 (8), p.721 |
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| language | eng |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Acetylation - drug effects Animals Apoptosis Cell Line, Tumor Dose-Response Relationship, Drug Enzyme Inhibitors - pharmacology HeLa Cells Histone Deacetylase Inhibitors Histone Deacetylases - metabolism Histones - metabolism Humans Hydroxamic Acids Mice Mice, Nude Neoplasms, Experimental - drug therapy Structure-Activity Relationship Sulfonamides Transplantation, Heterologous Xenograft Model Antitumor Assays |
| title | Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101 |
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