Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine
The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase β (Pol β...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2009-01, Vol.378 (3), p.419-423 |
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| creator | Frederick, Abbie M. Davis, Marguerite L. Rice, Kevin P. |
| description | The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation
in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase β (Pol β), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O
6 position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER
in vivo. Inhibition of the polymerase activity of Pol β may account for some of the synergism between Cloretazine’s two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol β, the enzyme’s lyase activity, which may also participate in BER, was not significantly inhibited. |
| doi_str_mv | 10.1016/j.bbrc.2008.11.042 |
| format | Article |
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in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase β (Pol β), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O
6 position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER
in vivo. Inhibition of the polymerase activity of Pol β may account for some of the synergism between Cloretazine’s two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol β, the enzyme’s lyase activity, which may also participate in BER, was not significantly inhibited.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/j.bbrc.2008.11.042</identifier><identifier>PMID: 19026985</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antineoplastic Agents - pharmacology ; Carbamoylation ; Cloretazine ; DNA alkylation ; DNA base excision repair ; DNA crosslinking agents ; DNA polymerase beta ; DNA Polymerase beta - antagonists & inhibitors ; DNA Polymerase I - antagonists & inhibitors ; DNA Repair - drug effects ; Humans ; Hydrazines - pharmacology ; Inhibitory Concentration 50 ; Methyl isocyanate ; Prodrugs - pharmacology ; Sulfonamides - pharmacology</subject><ispartof>Biochemical and biophysical research communications, 2009-01, Vol.378 (3), p.419-423</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c484t-ff7fe53eae7130b0d39f1b1086081504ba95edb44b1f7e7c4808854706abbd7d3</citedby><cites>FETCH-LOGICAL-c484t-ff7fe53eae7130b0d39f1b1086081504ba95edb44b1f7e7c4808854706abbd7d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bbrc.2008.11.042$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19026985$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Frederick, Abbie M.</creatorcontrib><creatorcontrib>Davis, Marguerite L.</creatorcontrib><creatorcontrib>Rice, Kevin P.</creatorcontrib><title>Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation
in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase β (Pol β), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O
6 position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER
in vivo. Inhibition of the polymerase activity of Pol β may account for some of the synergism between Cloretazine’s two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol β, the enzyme’s lyase activity, which may also participate in BER, was not significantly inhibited.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Carbamoylation</subject><subject>Cloretazine</subject><subject>DNA alkylation</subject><subject>DNA base excision repair</subject><subject>DNA crosslinking agents</subject><subject>DNA polymerase beta</subject><subject>DNA Polymerase beta - antagonists & inhibitors</subject><subject>DNA Polymerase I - antagonists & inhibitors</subject><subject>DNA Repair - drug effects</subject><subject>Humans</subject><subject>Hydrazines - pharmacology</subject><subject>Inhibitory Concentration 50</subject><subject>Methyl isocyanate</subject><subject>Prodrugs - pharmacology</subject><subject>Sulfonamides - pharmacology</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcuO1DAQRS0EYpqBH2CBvGKXUOU4LwkhjXp4jDSCzSCxs2ynMu1WEje201LzWXwI30SabvHYsKpF3XuqdC9jzxFyBKxebXNjgs0FQJMj5iDFA7ZCaCETCPIhWwFAlYkWv1ywJzFuARBl1T5mF9iCqNqmXLG7m2njjEvOT9z3fDOPeuLXH6_4zg-HkYKOxH9859omt3fpwM2Bpw1xPSVn9WQp8F3wXZjv-XrwgZL-5iZ6yh71eoj07Dwv2ed3b-_WH7LbT-9v1le3mZWNTFnf1z2VBWmqsQADXdH2aBCaChosQRrdltQZKQ32NdWLCZqmlDVU2piu7opL9ubE3c1mpM7SlIIe1C64UYeD8tqpfzeT26h7v1eiaUUjxQJ4eQYE_3WmmNTooqVh0BP5OSoBQpalLBahOAlt8DEG6n8fQVDHMtRWHctQxzIUooJf9Bd_v_fHck5_Ebw-CWgJae8oqGgdLal2LpBNqvPuf_yfMXKdvg</recordid><startdate>20090116</startdate><enddate>20090116</enddate><creator>Frederick, Abbie M.</creator><creator>Davis, Marguerite L.</creator><creator>Rice, Kevin P.</creator><general>Elsevier Inc</general><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>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20090116</creationdate><title>Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine</title><author>Frederick, Abbie M. ; Davis, Marguerite L. ; Rice, Kevin P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c484t-ff7fe53eae7130b0d39f1b1086081504ba95edb44b1f7e7c4808854706abbd7d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Carbamoylation</topic><topic>Cloretazine</topic><topic>DNA alkylation</topic><topic>DNA base excision repair</topic><topic>DNA crosslinking agents</topic><topic>DNA polymerase beta</topic><topic>DNA Polymerase beta - antagonists & inhibitors</topic><topic>DNA Polymerase I - antagonists & inhibitors</topic><topic>DNA Repair - drug effects</topic><topic>Humans</topic><topic>Hydrazines - pharmacology</topic><topic>Inhibitory Concentration 50</topic><topic>Methyl isocyanate</topic><topic>Prodrugs - pharmacology</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Frederick, Abbie M.</creatorcontrib><creatorcontrib>Davis, Marguerite L.</creatorcontrib><creatorcontrib>Rice, Kevin P.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Frederick, Abbie M.</au><au>Davis, Marguerite L.</au><au>Rice, Kevin P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2009-01-16</date><risdate>2009</risdate><volume>378</volume><issue>3</issue><spage>419</spage><epage>423</epage><pages>419-423</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation
in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase β (Pol β), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O
6 position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER
in vivo. Inhibition of the polymerase activity of Pol β may account for some of the synergism between Cloretazine’s two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol β, the enzyme’s lyase activity, which may also participate in BER, was not significantly inhibited.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19026985</pmid><doi>10.1016/j.bbrc.2008.11.042</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Biochemical and biophysical research communications, 2009-01, Vol.378 (3), p.419-423 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2892842 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Antineoplastic Agents - pharmacology Carbamoylation Cloretazine DNA alkylation DNA base excision repair DNA crosslinking agents DNA polymerase beta DNA Polymerase beta - antagonists & inhibitors DNA Polymerase I - antagonists & inhibitors DNA Repair - drug effects Humans Hydrazines - pharmacology Inhibitory Concentration 50 Methyl isocyanate Prodrugs - pharmacology Sulfonamides - pharmacology |
| title | Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine |
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