Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine
Cloretazine is an antitumor sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species. The cytotoxic potency of these species was analyzed in L1210 leukemia cells using analogues with chloroethylating or carbamoylating function only. Clonogenic assays showed that the...
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| creator | Ishiguro, Kimiko Seow, Helen A Penketh, Philip G Shyam, Krishnamurthy Sartorelli, Alan C |
| description | Cloretazine is an antitumor sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species. The
cytotoxic potency of these species was analyzed in L1210 leukemia cells using analogues with chloroethylating or carbamoylating
function only. Clonogenic assays showed that the chloroethylating-only agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine
(90CE) produced marked differential cytotoxicity against wild-type and O 6 -alkylguanine-DNA alkyltransferase–transfected L1210 cells (LC 10 , 1.4 versus 31 μmol/L), indicating that a large portion of the cytotoxicity was due to alkylation of DNA at the O-6 position
of guanine. Consistent with the concept that O-6 chloroethylation of DNA guanine progresses to interstrand cross-links, the
comet assay, in which DNA cross-links were measured by a reduction in DNA migration induced by strand breaks, showed that
cloretazine and 90CE, but not the carbamoylating-only agent 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE),
produced DNA cross-links and that cloretazine caused more DNA cross-links than 90CE at equimolar concentrations. Cell cycle
analyses showed that 90CE and 101MDCE at concentrations of 5 and 80 μmol/L, respectively, produced similar degrees of G 2 -M arrest. 90CE produced selective inhibition of DNA synthesis after overnight incubation, whereas 101MDCE caused rapid and
nonselective inhibition of RNA, DNA, and protein syntheses. Both 90CE and 101MDCE induced phosphorylation of histone H2AX,
albeit with distinct kinetics. These results indicate that ( a ) differential expression of O 6 -alkylguanine-DNA alkyltransferase in tumor and host cells seems to be responsible for tumor selectivity exerted by cloretazine;
( b ) 101MDCE enhances DNA cross-linking activity; and ( c ) 90CE induces cell death at concentrations lower than those causing alterations in the cell cycle and macromolecular syntheses.
[Mol Cancer Ther 2006;5(4):969–76] |
| doi_str_mv | 10.1158/1535-7163.MCT-05-0532 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2680221</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>16648568</sourcerecordid><originalsourceid>FETCH-LOGICAL-c440t-69826794e0ac39a8579e59f26867b255b5b2ea6e68cc38e0bf37628a2c0e9f163</originalsourceid><addsrcrecordid>eNpVkF1LwzAUhoMobn78BKVX3nUmaZMmN4IMv2DDm3kpIU1P28jWjLRT5q83tZsfcOAcTt73PeRB6ILgCSFMXBOWsDgjPJnMp4sYs1AJPUDjsBexYCQ9_J4HzQidtO0bxkRISo7RiHCeCsbFGL3OXQGRKyNtOuuafupqiEy9dN5BV2-XurNNFemmiIz2uV65_WrlLHQW2r1n7V3hN1VkghU6_WkbOENHpV62cL7rp-jl_m4xfYxnzw9P09tZbNIUdzGXgvJMpoC1SaQWLJPAZEm54FlOGctZTkFz4MKYRADOyyTjVGhqMMgy_O8U3Qy5602-gsJA03m9VGtvV9pvldNW_X9pbK0q967CCUwpCQFsCDDeta2H8sdLsOp5q56l6lmqwFthpnrewXf59_Cvawc4CK4GQW2r-sN6UEY3BryHFrQ3tWIqVZLL5Ato5oxD</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>American Association for Cancer Research</source><creator>Ishiguro, Kimiko ; Seow, Helen A ; Penketh, Philip G ; Shyam, Krishnamurthy ; Sartorelli, Alan C</creator><creatorcontrib>Ishiguro, Kimiko ; Seow, Helen A ; Penketh, Philip G ; Shyam, Krishnamurthy ; Sartorelli, Alan C</creatorcontrib><description>Cloretazine is an antitumor sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species. The
cytotoxic potency of these species was analyzed in L1210 leukemia cells using analogues with chloroethylating or carbamoylating
function only. Clonogenic assays showed that the chloroethylating-only agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine
(90CE) produced marked differential cytotoxicity against wild-type and O 6 -alkylguanine-DNA alkyltransferase–transfected L1210 cells (LC 10 , 1.4 versus 31 μmol/L), indicating that a large portion of the cytotoxicity was due to alkylation of DNA at the O-6 position
of guanine. Consistent with the concept that O-6 chloroethylation of DNA guanine progresses to interstrand cross-links, the
comet assay, in which DNA cross-links were measured by a reduction in DNA migration induced by strand breaks, showed that
cloretazine and 90CE, but not the carbamoylating-only agent 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE),
produced DNA cross-links and that cloretazine caused more DNA cross-links than 90CE at equimolar concentrations. Cell cycle
analyses showed that 90CE and 101MDCE at concentrations of 5 and 80 μmol/L, respectively, produced similar degrees of G 2 -M arrest. 90CE produced selective inhibition of DNA synthesis after overnight incubation, whereas 101MDCE caused rapid and
nonselective inhibition of RNA, DNA, and protein syntheses. Both 90CE and 101MDCE induced phosphorylation of histone H2AX,
albeit with distinct kinetics. These results indicate that ( a ) differential expression of O 6 -alkylguanine-DNA alkyltransferase in tumor and host cells seems to be responsible for tumor selectivity exerted by cloretazine;
( b ) 101MDCE enhances DNA cross-linking activity; and ( c ) 90CE induces cell death at concentrations lower than those causing alterations in the cell cycle and macromolecular syntheses.
[Mol Cancer Ther 2006;5(4):969–76]</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-05-0532</identifier><identifier>PMID: 16648568</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - toxicity ; Cell Cycle - drug effects ; Cell Survival - drug effects ; cloretazine ; Comet Assay ; DNA cross-links ; Histones - metabolism ; Hydrazines - chemistry ; Hydrazines - toxicity ; Leukemia L1210 ; Mice ; O-Methylguanine-DNA Methyltransferase - drug effects ; O-Methylguanine-DNA Methyltransferase - genetics ; O-Methylguanine-DNA Methyltransferase - metabolism ; O6-alkylguanine-DNA alkyltransferase ; Phosphorylation ; phosphorylation of histone H2AX ; Prodrugs ; Sulfonamides - chemistry ; Sulfonamides - toxicity ; Transfection</subject><ispartof>Molecular cancer therapeutics, 2006-04, Vol.5 (4), p.969-976</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c440t-69826794e0ac39a8579e59f26867b255b5b2ea6e68cc38e0bf37628a2c0e9f163</citedby><cites>FETCH-LOGICAL-c440t-69826794e0ac39a8579e59f26867b255b5b2ea6e68cc38e0bf37628a2c0e9f163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16648568$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishiguro, Kimiko</creatorcontrib><creatorcontrib>Seow, Helen A</creatorcontrib><creatorcontrib>Penketh, Philip G</creatorcontrib><creatorcontrib>Shyam, Krishnamurthy</creatorcontrib><creatorcontrib>Sartorelli, Alan C</creatorcontrib><title>Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Cloretazine is an antitumor sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species. The
cytotoxic potency of these species was analyzed in L1210 leukemia cells using analogues with chloroethylating or carbamoylating
function only. Clonogenic assays showed that the chloroethylating-only agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine
(90CE) produced marked differential cytotoxicity against wild-type and O 6 -alkylguanine-DNA alkyltransferase–transfected L1210 cells (LC 10 , 1.4 versus 31 μmol/L), indicating that a large portion of the cytotoxicity was due to alkylation of DNA at the O-6 position
of guanine. Consistent with the concept that O-6 chloroethylation of DNA guanine progresses to interstrand cross-links, the
comet assay, in which DNA cross-links were measured by a reduction in DNA migration induced by strand breaks, showed that
cloretazine and 90CE, but not the carbamoylating-only agent 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE),
produced DNA cross-links and that cloretazine caused more DNA cross-links than 90CE at equimolar concentrations. Cell cycle
analyses showed that 90CE and 101MDCE at concentrations of 5 and 80 μmol/L, respectively, produced similar degrees of G 2 -M arrest. 90CE produced selective inhibition of DNA synthesis after overnight incubation, whereas 101MDCE caused rapid and
nonselective inhibition of RNA, DNA, and protein syntheses. Both 90CE and 101MDCE induced phosphorylation of histone H2AX,
albeit with distinct kinetics. These results indicate that ( a ) differential expression of O 6 -alkylguanine-DNA alkyltransferase in tumor and host cells seems to be responsible for tumor selectivity exerted by cloretazine;
( b ) 101MDCE enhances DNA cross-linking activity; and ( c ) 90CE induces cell death at concentrations lower than those causing alterations in the cell cycle and macromolecular syntheses.
[Mol Cancer Ther 2006;5(4):969–76]</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>cloretazine</subject><subject>Comet Assay</subject><subject>DNA cross-links</subject><subject>Histones - metabolism</subject><subject>Hydrazines - chemistry</subject><subject>Hydrazines - toxicity</subject><subject>Leukemia L1210</subject><subject>Mice</subject><subject>O-Methylguanine-DNA Methyltransferase - drug effects</subject><subject>O-Methylguanine-DNA Methyltransferase - genetics</subject><subject>O-Methylguanine-DNA Methyltransferase - metabolism</subject><subject>O6-alkylguanine-DNA alkyltransferase</subject><subject>Phosphorylation</subject><subject>phosphorylation of histone H2AX</subject><subject>Prodrugs</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - toxicity</subject><subject>Transfection</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkF1LwzAUhoMobn78BKVX3nUmaZMmN4IMv2DDm3kpIU1P28jWjLRT5q83tZsfcOAcTt73PeRB6ILgCSFMXBOWsDgjPJnMp4sYs1AJPUDjsBexYCQ9_J4HzQidtO0bxkRISo7RiHCeCsbFGL3OXQGRKyNtOuuafupqiEy9dN5BV2-XurNNFemmiIz2uV65_WrlLHQW2r1n7V3hN1VkghU6_WkbOENHpV62cL7rp-jl_m4xfYxnzw9P09tZbNIUdzGXgvJMpoC1SaQWLJPAZEm54FlOGctZTkFz4MKYRADOyyTjVGhqMMgy_O8U3Qy5602-gsJA03m9VGtvV9pvldNW_X9pbK0q967CCUwpCQFsCDDeta2H8sdLsOp5q56l6lmqwFthpnrewXf59_Cvawc4CK4GQW2r-sN6UEY3BryHFrQ3tWIqVZLL5Ato5oxD</recordid><startdate>20060401</startdate><enddate>20060401</enddate><creator>Ishiguro, Kimiko</creator><creator>Seow, Helen A</creator><creator>Penketh, Philip G</creator><creator>Shyam, Krishnamurthy</creator><creator>Sartorelli, Alan C</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><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20060401</creationdate><title>Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine</title><author>Ishiguro, Kimiko ; Seow, Helen A ; Penketh, Philip G ; Shyam, Krishnamurthy ; Sartorelli, Alan C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c440t-69826794e0ac39a8579e59f26867b255b5b2ea6e68cc38e0bf37628a2c0e9f163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - toxicity</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>cloretazine</topic><topic>Comet Assay</topic><topic>DNA cross-links</topic><topic>Histones - metabolism</topic><topic>Hydrazines - chemistry</topic><topic>Hydrazines - toxicity</topic><topic>Leukemia L1210</topic><topic>Mice</topic><topic>O-Methylguanine-DNA Methyltransferase - drug effects</topic><topic>O-Methylguanine-DNA Methyltransferase - genetics</topic><topic>O-Methylguanine-DNA Methyltransferase - metabolism</topic><topic>O6-alkylguanine-DNA alkyltransferase</topic><topic>Phosphorylation</topic><topic>phosphorylation of histone H2AX</topic><topic>Prodrugs</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - toxicity</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishiguro, Kimiko</creatorcontrib><creatorcontrib>Seow, Helen A</creatorcontrib><creatorcontrib>Penketh, Philip G</creatorcontrib><creatorcontrib>Shyam, Krishnamurthy</creatorcontrib><creatorcontrib>Sartorelli, Alan C</creatorcontrib><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>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishiguro, Kimiko</au><au>Seow, Helen A</au><au>Penketh, Philip G</au><au>Shyam, Krishnamurthy</au><au>Sartorelli, Alan C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2006-04-01</date><risdate>2006</risdate><volume>5</volume><issue>4</issue><spage>969</spage><epage>976</epage><pages>969-976</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Cloretazine is an antitumor sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species. The
cytotoxic potency of these species was analyzed in L1210 leukemia cells using analogues with chloroethylating or carbamoylating
function only. Clonogenic assays showed that the chloroethylating-only agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine
(90CE) produced marked differential cytotoxicity against wild-type and O 6 -alkylguanine-DNA alkyltransferase–transfected L1210 cells (LC 10 , 1.4 versus 31 μmol/L), indicating that a large portion of the cytotoxicity was due to alkylation of DNA at the O-6 position
of guanine. Consistent with the concept that O-6 chloroethylation of DNA guanine progresses to interstrand cross-links, the
comet assay, in which DNA cross-links were measured by a reduction in DNA migration induced by strand breaks, showed that
cloretazine and 90CE, but not the carbamoylating-only agent 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE),
produced DNA cross-links and that cloretazine caused more DNA cross-links than 90CE at equimolar concentrations. Cell cycle
analyses showed that 90CE and 101MDCE at concentrations of 5 and 80 μmol/L, respectively, produced similar degrees of G 2 -M arrest. 90CE produced selective inhibition of DNA synthesis after overnight incubation, whereas 101MDCE caused rapid and
nonselective inhibition of RNA, DNA, and protein syntheses. Both 90CE and 101MDCE induced phosphorylation of histone H2AX,
albeit with distinct kinetics. These results indicate that ( a ) differential expression of O 6 -alkylguanine-DNA alkyltransferase in tumor and host cells seems to be responsible for tumor selectivity exerted by cloretazine;
( b ) 101MDCE enhances DNA cross-linking activity; and ( c ) 90CE induces cell death at concentrations lower than those causing alterations in the cell cycle and macromolecular syntheses.
[Mol Cancer Ther 2006;5(4):969–76]</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>16648568</pmid><doi>10.1158/1535-7163.MCT-05-0532</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1535-7163 |
| ispartof | Molecular cancer therapeutics, 2006-04, Vol.5 (4), p.969-976 |
| issn | 1535-7163 1538-8514 |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2680221 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - toxicity Cell Cycle - drug effects Cell Survival - drug effects cloretazine Comet Assay DNA cross-links Histones - metabolism Hydrazines - chemistry Hydrazines - toxicity Leukemia L1210 Mice O-Methylguanine-DNA Methyltransferase - drug effects O-Methylguanine-DNA Methyltransferase - genetics O-Methylguanine-DNA Methyltransferase - metabolism O6-alkylguanine-DNA alkyltransferase Phosphorylation phosphorylation of histone H2AX Prodrugs Sulfonamides - chemistry Sulfonamides - toxicity Transfection |
| title | Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine |
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