Identification of potent nontoxic poly(ADP-ribose) polymerase-1 inhibitors: Chemopotentiation and pharmacological studies
The nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) facilitates DNA repair, and is, therefore, an attractive target for anticancer chemo- and radio-potentiation. Novel benzimidazole-4-carboxamides (BZ1-6) and tricyclic lactam indoles (TI1-5) with PARP-1 K(i) values of
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| Veröffentlicht in: | Clinical cancer research 2003-07, Vol.9 (7), p.2711-2718 |
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| creator | CALABRESE, Christopher R BATEY, Michael A MAEGLEY, Karen CALVERT, Alan H HOSTOMSKY, Zdenek NEWELL, David R CURTIN, Nicola J THOMAS, Huw D DURKACZ, Barbara W WANG, Lan-Zhen KYLE, Suzanne SKALITZKY, Donald LI, Janke ZHANG, Catherine BORITZKI, Theodore |
| description | The nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) facilitates DNA repair, and is, therefore, an attractive target for anticancer chemo- and radio-potentiation. Novel benzimidazole-4-carboxamides (BZ1-6) and tricyclic lactam indoles (TI1-5) with PARP-1 K(i) values of |
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Novel benzimidazole-4-carboxamides (BZ1-6) and tricyclic lactam indoles (TI1-5) with PARP-1 K(i) values of <10 nM have been identified. Whole cell PARP-1 inhibition, intrinsic cell growth inhibition, and chemopotentiation of the cytotoxic agents temozolomide (TM) and topotecan (TP) were evaluated in LoVo human colon carcinoma cells. The acute toxicity of the inhibitors was investigated in PARP-1 null and wild-type mice. Tissue distribution and in vivo chemopotentiation activity was determined in nude mice bearing LoVo xenografts. At a nontoxic concentration (0.4 micro M) the PARP-1 inhibitors potentiated TM-induced growth inhibition 1.0-5.3-fold and TP-induced inhibition from 1.0-2.1-fold. Concentrations of the PARP-1 inhibitors that alone inhibited cell growth by 50% ranged from 8 to 94 micro M. Maximum potentiation of TM activity was achieved at nongrowth inhibitory concentrations (</=1 micro M) of potent PARP-1 inhibitors BZ5 and TI4. Whole cell PARP-1 inhibition by BZ3, BZ5, BZ6, TI1, and TI4 was confirmed by attenuation of DNA damage-induced NAD(+) depletion. Selected inhibitors (TI1, TI3, and TI4), in contrast to the benchmark compound PD128763, caused only mild hypothermia in both PARP-1 null and wild-type mice. Excellent distribution of BZ5, TI1, and TI3 into tumor tissue was observed, and TI3 enhanced TM antitumor activity in vivo. These studies have identified potent nontoxic PARP-1 inhibitors with structural modifications that promote aqueous solubility, tolerability, and tissue distribution. These compounds are important leads in the development of clinically viable PARP-1 inhibitors.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 12855651</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents, Alkylating - pharmacology ; Biological and medical sciences ; Cell Division ; Cell Line, Tumor ; Chemotherapy ; Dacarbazine - analogs & derivatives ; Dacarbazine - therapeutic use ; Dacarbazine - toxicity ; DNA Repair ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - pharmacology ; Humans ; Indoles - metabolism ; Kinetics ; Medical sciences ; Models, Chemical ; Pharmacology. Drug treatments ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases - genetics ; Temperature ; Time Factors ; Tissue Distribution ; Topotecan - therapeutic use ; Topotecan - toxicity</subject><ispartof>Clinical cancer research, 2003-07, Vol.9 (7), p.2711-2718</ispartof><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14995207$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12855651$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CALABRESE, Christopher R</creatorcontrib><creatorcontrib>BATEY, Michael A</creatorcontrib><creatorcontrib>MAEGLEY, Karen</creatorcontrib><creatorcontrib>CALVERT, Alan H</creatorcontrib><creatorcontrib>HOSTOMSKY, Zdenek</creatorcontrib><creatorcontrib>NEWELL, David R</creatorcontrib><creatorcontrib>CURTIN, Nicola J</creatorcontrib><creatorcontrib>THOMAS, Huw D</creatorcontrib><creatorcontrib>DURKACZ, Barbara W</creatorcontrib><creatorcontrib>WANG, Lan-Zhen</creatorcontrib><creatorcontrib>KYLE, Suzanne</creatorcontrib><creatorcontrib>SKALITZKY, Donald</creatorcontrib><creatorcontrib>LI, Janke</creatorcontrib><creatorcontrib>ZHANG, Catherine</creatorcontrib><creatorcontrib>BORITZKI, Theodore</creatorcontrib><title>Identification of potent nontoxic poly(ADP-ribose) polymerase-1 inhibitors: Chemopotentiation and pharmacological studies</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>The nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) facilitates DNA repair, and is, therefore, an attractive target for anticancer chemo- and radio-potentiation. Novel benzimidazole-4-carboxamides (BZ1-6) and tricyclic lactam indoles (TI1-5) with PARP-1 K(i) values of <10 nM have been identified. Whole cell PARP-1 inhibition, intrinsic cell growth inhibition, and chemopotentiation of the cytotoxic agents temozolomide (TM) and topotecan (TP) were evaluated in LoVo human colon carcinoma cells. The acute toxicity of the inhibitors was investigated in PARP-1 null and wild-type mice. Tissue distribution and in vivo chemopotentiation activity was determined in nude mice bearing LoVo xenografts. At a nontoxic concentration (0.4 micro M) the PARP-1 inhibitors potentiated TM-induced growth inhibition 1.0-5.3-fold and TP-induced inhibition from 1.0-2.1-fold. Concentrations of the PARP-1 inhibitors that alone inhibited cell growth by 50% ranged from 8 to 94 micro M. Maximum potentiation of TM activity was achieved at nongrowth inhibitory concentrations (</=1 micro M) of potent PARP-1 inhibitors BZ5 and TI4. Whole cell PARP-1 inhibition by BZ3, BZ5, BZ6, TI1, and TI4 was confirmed by attenuation of DNA damage-induced NAD(+) depletion. Selected inhibitors (TI1, TI3, and TI4), in contrast to the benchmark compound PD128763, caused only mild hypothermia in both PARP-1 null and wild-type mice. Excellent distribution of BZ5, TI1, and TI3 into tumor tissue was observed, and TI3 enhanced TM antitumor activity in vivo. These studies have identified potent nontoxic PARP-1 inhibitors with structural modifications that promote aqueous solubility, tolerability, and tissue distribution. These compounds are important leads in the development of clinically viable PARP-1 inhibitors.</description><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Division</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Dacarbazine - analogs & derivatives</subject><subject>Dacarbazine - therapeutic use</subject><subject>Dacarbazine - toxicity</subject><subject>DNA Repair</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Indoles - metabolism</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Models, Chemical</subject><subject>Pharmacology. Drug treatments</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Poly(ADP-ribose) Polymerases - genetics</subject><subject>Temperature</subject><subject>Time Factors</subject><subject>Tissue Distribution</subject><subject>Topotecan - therapeutic use</subject><subject>Topotecan - toxicity</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtLQzEQhYMotlb_gmQj6CKQd2_clfoqFHTRfcnNw0buTS5JCvbfe7EVVzNz-OacYc7AlAgxR4xKcT72eN4gzBmdgKtSvjAmnGB-CSaENkJIQabgsLIu1uCD0TWkCJOHQ6qjBGOKNX0HM87d4X7x9IFyaFNxD79C77IuDhEY4i60oaZcHuFy5_p0XA9HOx0tHHY699qkLn2OKR0sdW-DK9fgwuuuuJtTnYHNy_Nm-YbW76-r5WKNBspURZYYbxWxbWM9E8JpbLGSuOHScEW8FlRLKRnhTlFFW4KpUd7IhhPhfOPYDNwebYd92zu7HXLodT5s_14wAncnQJfxPJ91NKH8c1wpQfGc_QC3fGhs</recordid><startdate>20030701</startdate><enddate>20030701</enddate><creator>CALABRESE, Christopher R</creator><creator>BATEY, Michael A</creator><creator>MAEGLEY, Karen</creator><creator>CALVERT, Alan H</creator><creator>HOSTOMSKY, Zdenek</creator><creator>NEWELL, David R</creator><creator>CURTIN, Nicola J</creator><creator>THOMAS, Huw D</creator><creator>DURKACZ, Barbara W</creator><creator>WANG, Lan-Zhen</creator><creator>KYLE, Suzanne</creator><creator>SKALITZKY, Donald</creator><creator>LI, Janke</creator><creator>ZHANG, Catherine</creator><creator>BORITZKI, Theodore</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20030701</creationdate><title>Identification of potent nontoxic poly(ADP-ribose) polymerase-1 inhibitors: Chemopotentiation and pharmacological studies</title><author>CALABRESE, Christopher R ; BATEY, Michael A ; MAEGLEY, Karen ; CALVERT, Alan H ; HOSTOMSKY, Zdenek ; NEWELL, David R ; CURTIN, Nicola J ; THOMAS, Huw D ; DURKACZ, Barbara W ; WANG, Lan-Zhen ; KYLE, Suzanne ; SKALITZKY, Donald ; LI, Janke ; ZHANG, Catherine ; BORITZKI, Theodore</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p239t-d1cfd91db8df355ea0d0960846c491fa52a666314e9292b102c9fc68415ef8e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents, Alkylating - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Division</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Dacarbazine - analogs & derivatives</topic><topic>Dacarbazine - therapeutic use</topic><topic>Dacarbazine - toxicity</topic><topic>DNA Repair</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Indoles - metabolism</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Models, Chemical</topic><topic>Pharmacology. Drug treatments</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors</topic><topic>Poly(ADP-ribose) Polymerases - genetics</topic><topic>Temperature</topic><topic>Time Factors</topic><topic>Tissue Distribution</topic><topic>Topotecan - therapeutic use</topic><topic>Topotecan - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CALABRESE, Christopher R</creatorcontrib><creatorcontrib>BATEY, Michael A</creatorcontrib><creatorcontrib>MAEGLEY, Karen</creatorcontrib><creatorcontrib>CALVERT, Alan H</creatorcontrib><creatorcontrib>HOSTOMSKY, Zdenek</creatorcontrib><creatorcontrib>NEWELL, David R</creatorcontrib><creatorcontrib>CURTIN, Nicola J</creatorcontrib><creatorcontrib>THOMAS, Huw D</creatorcontrib><creatorcontrib>DURKACZ, Barbara W</creatorcontrib><creatorcontrib>WANG, Lan-Zhen</creatorcontrib><creatorcontrib>KYLE, Suzanne</creatorcontrib><creatorcontrib>SKALITZKY, Donald</creatorcontrib><creatorcontrib>LI, Janke</creatorcontrib><creatorcontrib>ZHANG, Catherine</creatorcontrib><creatorcontrib>BORITZKI, Theodore</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CALABRESE, Christopher R</au><au>BATEY, Michael A</au><au>MAEGLEY, Karen</au><au>CALVERT, Alan H</au><au>HOSTOMSKY, Zdenek</au><au>NEWELL, David R</au><au>CURTIN, Nicola J</au><au>THOMAS, Huw D</au><au>DURKACZ, Barbara W</au><au>WANG, Lan-Zhen</au><au>KYLE, Suzanne</au><au>SKALITZKY, Donald</au><au>LI, Janke</au><au>ZHANG, Catherine</au><au>BORITZKI, Theodore</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of potent nontoxic poly(ADP-ribose) polymerase-1 inhibitors: Chemopotentiation and pharmacological studies</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2003-07-01</date><risdate>2003</risdate><volume>9</volume><issue>7</issue><spage>2711</spage><epage>2718</epage><pages>2711-2718</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>The nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) facilitates DNA repair, and is, therefore, an attractive target for anticancer chemo- and radio-potentiation. Novel benzimidazole-4-carboxamides (BZ1-6) and tricyclic lactam indoles (TI1-5) with PARP-1 K(i) values of <10 nM have been identified. Whole cell PARP-1 inhibition, intrinsic cell growth inhibition, and chemopotentiation of the cytotoxic agents temozolomide (TM) and topotecan (TP) were evaluated in LoVo human colon carcinoma cells. The acute toxicity of the inhibitors was investigated in PARP-1 null and wild-type mice. Tissue distribution and in vivo chemopotentiation activity was determined in nude mice bearing LoVo xenografts. At a nontoxic concentration (0.4 micro M) the PARP-1 inhibitors potentiated TM-induced growth inhibition 1.0-5.3-fold and TP-induced inhibition from 1.0-2.1-fold. Concentrations of the PARP-1 inhibitors that alone inhibited cell growth by 50% ranged from 8 to 94 micro M. Maximum potentiation of TM activity was achieved at nongrowth inhibitory concentrations (</=1 micro M) of potent PARP-1 inhibitors BZ5 and TI4. Whole cell PARP-1 inhibition by BZ3, BZ5, BZ6, TI1, and TI4 was confirmed by attenuation of DNA damage-induced NAD(+) depletion. Selected inhibitors (TI1, TI3, and TI4), in contrast to the benchmark compound PD128763, caused only mild hypothermia in both PARP-1 null and wild-type mice. Excellent distribution of BZ5, TI1, and TI3 into tumor tissue was observed, and TI3 enhanced TM antitumor activity in vivo. These studies have identified potent nontoxic PARP-1 inhibitors with structural modifications that promote aqueous solubility, tolerability, and tissue distribution. These compounds are important leads in the development of clinically viable PARP-1 inhibitors.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>12855651</pmid><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2003-07, Vol.9 (7), p.2711-2718 |
| issn | 1078-0432 1557-3265 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Antineoplastic agents Antineoplastic Agents - pharmacology Antineoplastic Agents, Alkylating - pharmacology Biological and medical sciences Cell Division Cell Line, Tumor Chemotherapy Dacarbazine - analogs & derivatives Dacarbazine - therapeutic use Dacarbazine - toxicity DNA Repair Dose-Response Relationship, Drug Enzyme Inhibitors - pharmacology Humans Indoles - metabolism Kinetics Medical sciences Models, Chemical Pharmacology. Drug treatments Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases - genetics Temperature Time Factors Tissue Distribution Topotecan - therapeutic use Topotecan - toxicity |
| title | Identification of potent nontoxic poly(ADP-ribose) polymerase-1 inhibitors: Chemopotentiation and pharmacological studies |
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