Anticancer chemosensitization and radiosensitization by the novel Poly(ADP-ribose) polymerase-1 inhibitor AG14361
Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel po...
Gespeichert in:
Veröffentlicht in: | JNCI : Journal of the National Cancer Institute 2004-01, Vol.96 (1), p.56-67 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 67 |
---|---|
container_issue | 1 |
container_start_page | 56 |
container_title | JNCI : Journal of the National Cancer Institute |
container_volume | 96 |
creator | CALABRESE, Christopher R ALMASSY, Robert LI, Jianke MAEGLEY, Karen NEWELL, David R NOTARIANNI, Elena STRATFORD, Ian J SKALITZKY, Donald THOMAS, Huw D WANG, Ian-Zhen WEBBER, Stephen E WILLIAMS, Kaye J BARTON, Stephanie CURTIN, Nicola J BATEY, Michael A CALVERT, A. Hilary CANAN-KOCH, Stacie DURKACZ, Barbara W HOSTOMSKY, Zdenek KUMPF, Robert A KYLE, Suzanne |
description | Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant |
doi_str_mv | 10.1093/jnci/djh005 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_221039108</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>526889661</sourcerecordid><originalsourceid>FETCH-LOGICAL-c447t-c97a54205024fd3cbf98d1d548fc7f506f5ed42fb77a97e54aabce132f73fb9e3</originalsourceid><addsrcrecordid>eNpd0M9LwzAUwPEgipvTk3cJgqBIXX4uzbFMncLAHfRc0jShKVs6k06Yf70ZGwzM5cHjwwt8AbjG6AkjScet125ctw1C_AQMMZugjGDET8EQISKyPBdsAC5ibFF6krBzMMBMICmoHILvwvdOK69NgLoxqy4aH13vflXvOg-Vr2FQtfu3rrawbwz03Y9ZwkW33N4Xz4ssuCq5B7hOi5UJKpoMQ-cbV7m-C7CYYUYn-BKcWbWM5uowR-Dr9eVz-pbNP2bv02KeacZEn2kpFGcEcUSYramurMxrXHOWWy0sRxPLTc2IrYRQUhjOlKq0wZRYQW0lDR2B2_3ddei-Nyb2Zdttgk9fliT1oRKjPKHHPdKhizEYW66DW6mwLTEqd3XLXd1yXzfpm8PJTbUy9dEeciZwdwAqarW0IYV18ei4JGJCOP0DzGSEmg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>221039108</pqid></control><display><type>article</type><title>Anticancer chemosensitization and radiosensitization by the novel Poly(ADP-ribose) polymerase-1 inhibitor AG14361</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>CALABRESE, Christopher R ; ALMASSY, Robert ; LI, Jianke ; MAEGLEY, Karen ; NEWELL, David R ; NOTARIANNI, Elena ; STRATFORD, Ian J ; SKALITZKY, Donald ; THOMAS, Huw D ; WANG, Ian-Zhen ; WEBBER, Stephen E ; WILLIAMS, Kaye J ; BARTON, Stephanie ; CURTIN, Nicola J ; BATEY, Michael A ; CALVERT, A. Hilary ; CANAN-KOCH, Stacie ; DURKACZ, Barbara W ; HOSTOMSKY, Zdenek ; KUMPF, Robert A ; KYLE, Suzanne</creator><creatorcontrib>CALABRESE, Christopher R ; ALMASSY, Robert ; LI, Jianke ; MAEGLEY, Karen ; NEWELL, David R ; NOTARIANNI, Elena ; STRATFORD, Ian J ; SKALITZKY, Donald ; THOMAS, Huw D ; WANG, Ian-Zhen ; WEBBER, Stephen E ; WILLIAMS, Kaye J ; BARTON, Stephanie ; CURTIN, Nicola J ; BATEY, Michael A ; CALVERT, A. Hilary ; CANAN-KOCH, Stacie ; DURKACZ, Barbara W ; HOSTOMSKY, Zdenek ; KUMPF, Robert A ; KYLE, Suzanne</creatorcontrib><description>Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts.
The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or gamma-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1-/- and PARP-1+/+ cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided.
AG14361 at 0.4 micro M did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] = 4.9-fold to 5.9-fold; P =.004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI = 1.3-fold to 1.9-fold; P =.002) and inhibited recovery from potentially lethal gamma-radiation damage in LoVo cells by 73% (95% CI = 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two- to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours.
AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.</description><identifier>ISSN: 0027-8874</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/djh005</identifier><identifier>PMID: 14709739</identifier><identifier>CODEN: JNCIEQ</identifier><language>eng</language><publisher>Cary, NC: Oxford University Press</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Azulenes ; Benzodiazepines - pharmacology ; Biological and medical sciences ; Cancer ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - radiotherapy ; Cell Line, Tumor ; Chemotherapy ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - radiotherapy ; Dacarbazine - analogs & derivatives ; Dacarbazine - pharmacology ; Diseases of the digestive system ; Drug Resistance, Neoplasm - drug effects ; Enzyme Inhibitors - pharmacology ; Gamma Rays - therapeutic use ; Gene Expression Regulation, Enzymologic - drug effects ; Gene Expression Regulation, Neoplastic - drug effects ; General aspects ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - radiotherapy ; Medical research ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases - metabolism ; Radiation-Sensitizing Agents - pharmacology ; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects) ; Temozolomide ; Transplantation, Heterologous</subject><ispartof>JNCI : Journal of the National Cancer Institute, 2004-01, Vol.96 (1), p.56-67</ispartof><rights>2004 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Jan 7, 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-c97a54205024fd3cbf98d1d548fc7f506f5ed42fb77a97e54aabce132f73fb9e3</citedby><cites>FETCH-LOGICAL-c447t-c97a54205024fd3cbf98d1d548fc7f506f5ed42fb77a97e54aabce132f73fb9e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15927625$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14709739$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CALABRESE, Christopher R</creatorcontrib><creatorcontrib>ALMASSY, Robert</creatorcontrib><creatorcontrib>LI, Jianke</creatorcontrib><creatorcontrib>MAEGLEY, Karen</creatorcontrib><creatorcontrib>NEWELL, David R</creatorcontrib><creatorcontrib>NOTARIANNI, Elena</creatorcontrib><creatorcontrib>STRATFORD, Ian J</creatorcontrib><creatorcontrib>SKALITZKY, Donald</creatorcontrib><creatorcontrib>THOMAS, Huw D</creatorcontrib><creatorcontrib>WANG, Ian-Zhen</creatorcontrib><creatorcontrib>WEBBER, Stephen E</creatorcontrib><creatorcontrib>WILLIAMS, Kaye J</creatorcontrib><creatorcontrib>BARTON, Stephanie</creatorcontrib><creatorcontrib>CURTIN, Nicola J</creatorcontrib><creatorcontrib>BATEY, Michael A</creatorcontrib><creatorcontrib>CALVERT, A. Hilary</creatorcontrib><creatorcontrib>CANAN-KOCH, Stacie</creatorcontrib><creatorcontrib>DURKACZ, Barbara W</creatorcontrib><creatorcontrib>HOSTOMSKY, Zdenek</creatorcontrib><creatorcontrib>KUMPF, Robert A</creatorcontrib><creatorcontrib>KYLE, Suzanne</creatorcontrib><title>Anticancer chemosensitization and radiosensitization by the novel Poly(ADP-ribose) polymerase-1 inhibitor AG14361</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>J Natl Cancer Inst</addtitle><description>Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts.
The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or gamma-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1-/- and PARP-1+/+ cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided.
AG14361 at 0.4 micro M did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] = 4.9-fold to 5.9-fold; P =.004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI = 1.3-fold to 1.9-fold; P =.002) and inhibited recovery from potentially lethal gamma-radiation damage in LoVo cells by 73% (95% CI = 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two- to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours.
AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Azulenes</subject><subject>Benzodiazepines - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - radiotherapy</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - radiotherapy</subject><subject>Dacarbazine - analogs & derivatives</subject><subject>Dacarbazine - pharmacology</subject><subject>Diseases of the digestive system</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gamma Rays - therapeutic use</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>General aspects</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - radiotherapy</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Radiation-Sensitizing Agents - pharmacology</subject><subject>Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects)</subject><subject>Temozolomide</subject><subject>Transplantation, Heterologous</subject><issn>0027-8874</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0M9LwzAUwPEgipvTk3cJgqBIXX4uzbFMncLAHfRc0jShKVs6k06Yf70ZGwzM5cHjwwt8AbjG6AkjScet125ctw1C_AQMMZugjGDET8EQISKyPBdsAC5ibFF6krBzMMBMICmoHILvwvdOK69NgLoxqy4aH13vflXvOg-Vr2FQtfu3rrawbwz03Y9ZwkW33N4Xz4ssuCq5B7hOi5UJKpoMQ-cbV7m-C7CYYUYn-BKcWbWM5uowR-Dr9eVz-pbNP2bv02KeacZEn2kpFGcEcUSYramurMxrXHOWWy0sRxPLTc2IrYRQUhjOlKq0wZRYQW0lDR2B2_3ddei-Nyb2Zdttgk9fliT1oRKjPKHHPdKhizEYW66DW6mwLTEqd3XLXd1yXzfpm8PJTbUy9dEeciZwdwAqarW0IYV18ei4JGJCOP0DzGSEmg</recordid><startdate>20040107</startdate><enddate>20040107</enddate><creator>CALABRESE, Christopher R</creator><creator>ALMASSY, Robert</creator><creator>LI, Jianke</creator><creator>MAEGLEY, Karen</creator><creator>NEWELL, David R</creator><creator>NOTARIANNI, Elena</creator><creator>STRATFORD, Ian J</creator><creator>SKALITZKY, Donald</creator><creator>THOMAS, Huw D</creator><creator>WANG, Ian-Zhen</creator><creator>WEBBER, Stephen E</creator><creator>WILLIAMS, Kaye J</creator><creator>BARTON, Stephanie</creator><creator>CURTIN, Nicola J</creator><creator>BATEY, Michael A</creator><creator>CALVERT, A. Hilary</creator><creator>CANAN-KOCH, Stacie</creator><creator>DURKACZ, Barbara W</creator><creator>HOSTOMSKY, Zdenek</creator><creator>KUMPF, Robert A</creator><creator>KYLE, Suzanne</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</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>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20040107</creationdate><title>Anticancer chemosensitization and radiosensitization by the novel Poly(ADP-ribose) polymerase-1 inhibitor AG14361</title><author>CALABRESE, Christopher R ; ALMASSY, Robert ; LI, Jianke ; MAEGLEY, Karen ; NEWELL, David R ; NOTARIANNI, Elena ; STRATFORD, Ian J ; SKALITZKY, Donald ; THOMAS, Huw D ; WANG, Ian-Zhen ; WEBBER, Stephen E ; WILLIAMS, Kaye J ; BARTON, Stephanie ; CURTIN, Nicola J ; BATEY, Michael A ; CALVERT, A. Hilary ; CANAN-KOCH, Stacie ; DURKACZ, Barbara W ; HOSTOMSKY, Zdenek ; KUMPF, Robert A ; KYLE, Suzanne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-c97a54205024fd3cbf98d1d548fc7f506f5ed42fb77a97e54aabce132f73fb9e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Azulenes</topic><topic>Benzodiazepines - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - radiotherapy</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - radiotherapy</topic><topic>Dacarbazine - analogs & derivatives</topic><topic>Dacarbazine - pharmacology</topic><topic>Diseases of the digestive system</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gamma Rays - therapeutic use</topic><topic>Gene Expression Regulation, Enzymologic - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>General aspects</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - radiotherapy</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Radiation-Sensitizing Agents - pharmacology</topic><topic>Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects)</topic><topic>Temozolomide</topic><topic>Transplantation, Heterologous</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CALABRESE, Christopher R</creatorcontrib><creatorcontrib>ALMASSY, Robert</creatorcontrib><creatorcontrib>LI, Jianke</creatorcontrib><creatorcontrib>MAEGLEY, Karen</creatorcontrib><creatorcontrib>NEWELL, David R</creatorcontrib><creatorcontrib>NOTARIANNI, Elena</creatorcontrib><creatorcontrib>STRATFORD, Ian J</creatorcontrib><creatorcontrib>SKALITZKY, Donald</creatorcontrib><creatorcontrib>THOMAS, Huw D</creatorcontrib><creatorcontrib>WANG, Ian-Zhen</creatorcontrib><creatorcontrib>WEBBER, Stephen E</creatorcontrib><creatorcontrib>WILLIAMS, Kaye J</creatorcontrib><creatorcontrib>BARTON, Stephanie</creatorcontrib><creatorcontrib>CURTIN, Nicola J</creatorcontrib><creatorcontrib>BATEY, Michael A</creatorcontrib><creatorcontrib>CALVERT, A. Hilary</creatorcontrib><creatorcontrib>CANAN-KOCH, Stacie</creatorcontrib><creatorcontrib>DURKACZ, Barbara W</creatorcontrib><creatorcontrib>HOSTOMSKY, Zdenek</creatorcontrib><creatorcontrib>KUMPF, Robert A</creatorcontrib><creatorcontrib>KYLE, Suzanne</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>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>JNCI : Journal of the National Cancer Institute</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CALABRESE, Christopher R</au><au>ALMASSY, Robert</au><au>LI, Jianke</au><au>MAEGLEY, Karen</au><au>NEWELL, David R</au><au>NOTARIANNI, Elena</au><au>STRATFORD, Ian J</au><au>SKALITZKY, Donald</au><au>THOMAS, Huw D</au><au>WANG, Ian-Zhen</au><au>WEBBER, Stephen E</au><au>WILLIAMS, Kaye J</au><au>BARTON, Stephanie</au><au>CURTIN, Nicola J</au><au>BATEY, Michael A</au><au>CALVERT, A. Hilary</au><au>CANAN-KOCH, Stacie</au><au>DURKACZ, Barbara W</au><au>HOSTOMSKY, Zdenek</au><au>KUMPF, Robert A</au><au>KYLE, Suzanne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anticancer chemosensitization and radiosensitization by the novel Poly(ADP-ribose) polymerase-1 inhibitor AG14361</atitle><jtitle>JNCI : Journal of the National Cancer Institute</jtitle><addtitle>J Natl Cancer Inst</addtitle><date>2004-01-07</date><risdate>2004</risdate><volume>96</volume><issue>1</issue><spage>56</spage><epage>67</epage><pages>56-67</pages><issn>0027-8874</issn><eissn>1460-2105</eissn><coden>JNCIEQ</coden><abstract>Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts.
The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or gamma-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1-/- and PARP-1+/+ cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided.
AG14361 at 0.4 micro M did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] = 4.9-fold to 5.9-fold; P =.004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI = 1.3-fold to 1.9-fold; P =.002) and inhibited recovery from potentially lethal gamma-radiation damage in LoVo cells by 73% (95% CI = 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two- to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours.
AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.</abstract><cop>Cary, NC</cop><pub>Oxford University Press</pub><pmid>14709739</pmid><doi>10.1093/jnci/djh005</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0027-8874 |
ispartof | JNCI : Journal of the National Cancer Institute, 2004-01, Vol.96 (1), p.56-67 |
issn | 0027-8874 1460-2105 |
language | eng |
recordid | cdi_proquest_journals_221039108 |
source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
subjects | Animals Antineoplastic agents Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Azulenes Benzodiazepines - pharmacology Biological and medical sciences Cancer Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - radiotherapy Cell Line, Tumor Chemotherapy Colorectal Neoplasms - drug therapy Colorectal Neoplasms - radiotherapy Dacarbazine - analogs & derivatives Dacarbazine - pharmacology Diseases of the digestive system Drug Resistance, Neoplasm - drug effects Enzyme Inhibitors - pharmacology Gamma Rays - therapeutic use Gene Expression Regulation, Enzymologic - drug effects Gene Expression Regulation, Neoplastic - drug effects General aspects Humans Lung Neoplasms - drug therapy Lung Neoplasms - radiotherapy Medical research Medical sciences Mice Pharmacology. Drug treatments Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases - metabolism Radiation-Sensitizing Agents - pharmacology Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects) Temozolomide Transplantation, Heterologous |
title | Anticancer chemosensitization and radiosensitization by the novel Poly(ADP-ribose) polymerase-1 inhibitor AG14361 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T17%3A40%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Anticancer%20chemosensitization%20and%20radiosensitization%20by%20the%20novel%20Poly(ADP-ribose)%20polymerase-1%20inhibitor%20AG14361&rft.jtitle=JNCI%20:%20Journal%20of%20the%20National%20Cancer%20Institute&rft.au=CALABRESE,%20Christopher%20R&rft.date=2004-01-07&rft.volume=96&rft.issue=1&rft.spage=56&rft.epage=67&rft.pages=56-67&rft.issn=0027-8874&rft.eissn=1460-2105&rft.coden=JNCIEQ&rft_id=info:doi/10.1093/jnci/djh005&rft_dat=%3Cproquest_cross%3E526889661%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=221039108&rft_id=info:pmid/14709739&rfr_iscdi=true |