Effects of alkylating metabolites of ifosfamide and its bromo analogues on DNA of HeLa cells
The in vitro cytotoxicity and mechanism of action of three alkylating compounds: an active metabolite of ifosfamide ( 1, isophosphoramide mustard, N, N'-bis(2-chloroethyl)phosphorodiamidic acid) and its bromo substituted analogues, 2 (one chlorine atom replaced by bromine atom) and 3 (two chlor...
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| Veröffentlicht in: | Biochemical pharmacology 1992-03, Vol.43 (5), p.937-943 |
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| container_title | Biochemical pharmacology |
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| creator | Studzian, Kazimierz Kinas, Ryszard Ciesielska, Ewa Szmigiero, Leszek |
| description | The
in vitro cytotoxicity and mechanism of action of three alkylating compounds: an active metabolite of ifosfamide (
1, isophosphoramide mustard,
N,
N'-bis(2-chloroethyl)phosphorodiamidic acid) and its bromo substituted analogues,
2 (one chlorine atom replaced by bromine atom) and
3 (two chlorine atoms replaced by bromine atoms), were studied in cultured HeLa cells. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent interstrand crosslinks, DNA-protein crosslinks and alkali-labile sites (ALSs) in HeLa cells following a 1 hr exposure to the compounds. The bromo analogues were more cytotoxic than 1 and exhibited higher crosslinking potency. The time-course of crosslink formation and removal for the three compounds was similar. ALSs in DNA were produced by all tested drugs but
3 exhibited exceptionally high activity and was able to induce two kinds of alkali-labile lesion (fast- and slow-appearing) whereas
1 and
2 generated only slow-appearing ones. The results suggest that
1 and
2 are more specific in their reaction with DNA in that they produced a lesser variety of lesions than
3. A potential advantage of
2 over
1 seems to be its higher DNA interstrand crosslinking activity. |
| doi_str_mv | 10.1016/0006-2952(92)90596-B |
| format | Article |
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in vitro cytotoxicity and mechanism of action of three alkylating compounds: an active metabolite of ifosfamide (
1, isophosphoramide mustard,
N,
N'-bis(2-chloroethyl)phosphorodiamidic acid) and its bromo substituted analogues,
2 (one chlorine atom replaced by bromine atom) and
3 (two chlorine atoms replaced by bromine atoms), were studied in cultured HeLa cells. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent interstrand crosslinks, DNA-protein crosslinks and alkali-labile sites (ALSs) in HeLa cells following a 1 hr exposure to the compounds. The bromo analogues were more cytotoxic than 1 and exhibited higher crosslinking potency. The time-course of crosslink formation and removal for the three compounds was similar. ALSs in DNA were produced by all tested drugs but
3 exhibited exceptionally high activity and was able to induce two kinds of alkali-labile lesion (fast- and slow-appearing) whereas
1 and
2 generated only slow-appearing ones. The results suggest that
1 and
2 are more specific in their reaction with DNA in that they produced a lesser variety of lesions than
3. A potential advantage of
2 over
1 seems to be its higher DNA interstrand crosslinking activity.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/0006-2952(92)90596-B</identifier><identifier>PMID: 1554391</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Antineoplastic agents ; Biological and medical sciences ; Cell Division - drug effects ; Cell Survival - drug effects ; Cross-Linking Reagents ; DNA, Neoplasm - drug effects ; Dose-Response Relationship, Drug ; General aspects ; HeLa Cells - drug effects ; Humans ; Ifosfamide - analogs & derivatives ; Ifosfamide - pharmacology ; Medical sciences ; Pharmacology. Drug treatments ; Phosphoramide Mustards - pharmacology</subject><ispartof>Biochemical pharmacology, 1992-03, Vol.43 (5), p.937-943</ispartof><rights>1992</rights><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-99a19b98bc0955aaaabc70bb6f7f7a692ed6502bf734bb1ff1d48d117beea6333</citedby><cites>FETCH-LOGICAL-c386t-99a19b98bc0955aaaabc70bb6f7f7a692ed6502bf734bb1ff1d48d117beea6333</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/0006-2952(92)90596-B$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5325097$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1554391$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Studzian, Kazimierz</creatorcontrib><creatorcontrib>Kinas, Ryszard</creatorcontrib><creatorcontrib>Ciesielska, Ewa</creatorcontrib><creatorcontrib>Szmigiero, Leszek</creatorcontrib><title>Effects of alkylating metabolites of ifosfamide and its bromo analogues on DNA of HeLa cells</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>The
in vitro cytotoxicity and mechanism of action of three alkylating compounds: an active metabolite of ifosfamide (
1, isophosphoramide mustard,
N,
N'-bis(2-chloroethyl)phosphorodiamidic acid) and its bromo substituted analogues,
2 (one chlorine atom replaced by bromine atom) and
3 (two chlorine atoms replaced by bromine atoms), were studied in cultured HeLa cells. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent interstrand crosslinks, DNA-protein crosslinks and alkali-labile sites (ALSs) in HeLa cells following a 1 hr exposure to the compounds. The bromo analogues were more cytotoxic than 1 and exhibited higher crosslinking potency. The time-course of crosslink formation and removal for the three compounds was similar. ALSs in DNA were produced by all tested drugs but
3 exhibited exceptionally high activity and was able to induce two kinds of alkali-labile lesion (fast- and slow-appearing) whereas
1 and
2 generated only slow-appearing ones. The results suggest that
1 and
2 are more specific in their reaction with DNA in that they produced a lesser variety of lesions than
3. A potential advantage of
2 over
1 seems to be its higher DNA interstrand crosslinking activity.</description><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Division - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cross-Linking Reagents</subject><subject>DNA, Neoplasm - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>General aspects</subject><subject>HeLa Cells - drug effects</subject><subject>Humans</subject><subject>Ifosfamide - analogs & derivatives</subject><subject>Ifosfamide - pharmacology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphoramide Mustards - pharmacology</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kVFLHDEUhYMoulr_gcI8SLEP0yaZSWbyUtCt1cLSvrRvQrjJ3EjamYkms8L-ezPdRd8MgXDv-e7lcELIGaOfGWXyC6VUllwJfqn4J0WFkuX1HlmwtqlyW7b7ZPGKHJHjlP7OZSvZITlkQtSVYgtyf-Mc2ikVwRXQ_9v0MPnxoRhwAhN6P-F_xbuQHAy-wwLGrvCZNzEMIVfQh4f1TI3Ft59XM3yHKygs9n36QA4c9AlPd-8J-fP95vfyrlz9uv2xvFqVtmrlVCoFTBnVGkuVEJCPsQ01RrrGNSAVx04Kyo1rqtoY5hzr6rZjrDGIIKuqOiEft3sfY3jKZiY9-DQ7gBHDOumGt7JuOc9gvQVtDClFdPox-gHiRjOq51D1HJGeE9Mq3zlUfZ3Hznf712bA7m1om2LWL3Y6JAu9izBan14xUXFBVZOxr1sMcxbPHqNO1uNosfMx_4Hugn_fxwvs-5Mv</recordid><startdate>19920303</startdate><enddate>19920303</enddate><creator>Studzian, Kazimierz</creator><creator>Kinas, Ryszard</creator><creator>Ciesielska, Ewa</creator><creator>Szmigiero, Leszek</creator><general>Elsevier Inc</general><general>Elsevier Science</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>7X8</scope></search><sort><creationdate>19920303</creationdate><title>Effects of alkylating metabolites of ifosfamide and its bromo analogues on DNA of HeLa cells</title><author>Studzian, Kazimierz ; Kinas, Ryszard ; Ciesielska, Ewa ; Szmigiero, Leszek</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-99a19b98bc0955aaaabc70bb6f7f7a692ed6502bf734bb1ff1d48d117beea6333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Division - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Cross-Linking Reagents</topic><topic>DNA, Neoplasm - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>General aspects</topic><topic>HeLa Cells - drug effects</topic><topic>Humans</topic><topic>Ifosfamide - analogs & derivatives</topic><topic>Ifosfamide - pharmacology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphoramide Mustards - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Studzian, Kazimierz</creatorcontrib><creatorcontrib>Kinas, Ryszard</creatorcontrib><creatorcontrib>Ciesielska, Ewa</creatorcontrib><creatorcontrib>Szmigiero, Leszek</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>MEDLINE - Academic</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Studzian, Kazimierz</au><au>Kinas, Ryszard</au><au>Ciesielska, Ewa</au><au>Szmigiero, Leszek</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of alkylating metabolites of ifosfamide and its bromo analogues on DNA of HeLa cells</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>1992-03-03</date><risdate>1992</risdate><volume>43</volume><issue>5</issue><spage>937</spage><epage>943</epage><pages>937-943</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>The
in vitro cytotoxicity and mechanism of action of three alkylating compounds: an active metabolite of ifosfamide (
1, isophosphoramide mustard,
N,
N'-bis(2-chloroethyl)phosphorodiamidic acid) and its bromo substituted analogues,
2 (one chlorine atom replaced by bromine atom) and
3 (two chlorine atoms replaced by bromine atoms), were studied in cultured HeLa cells. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent interstrand crosslinks, DNA-protein crosslinks and alkali-labile sites (ALSs) in HeLa cells following a 1 hr exposure to the compounds. The bromo analogues were more cytotoxic than 1 and exhibited higher crosslinking potency. The time-course of crosslink formation and removal for the three compounds was similar. ALSs in DNA were produced by all tested drugs but
3 exhibited exceptionally high activity and was able to induce two kinds of alkali-labile lesion (fast- and slow-appearing) whereas
1 and
2 generated only slow-appearing ones. The results suggest that
1 and
2 are more specific in their reaction with DNA in that they produced a lesser variety of lesions than
3. A potential advantage of
2 over
1 seems to be its higher DNA interstrand crosslinking activity.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>1554391</pmid><doi>10.1016/0006-2952(92)90596-B</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0006-2952 |
| ispartof | Biochemical pharmacology, 1992-03, Vol.43 (5), p.937-943 |
| issn | 0006-2952 1873-2968 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_72864822 |
| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Antineoplastic agents Biological and medical sciences Cell Division - drug effects Cell Survival - drug effects Cross-Linking Reagents DNA, Neoplasm - drug effects Dose-Response Relationship, Drug General aspects HeLa Cells - drug effects Humans Ifosfamide - analogs & derivatives Ifosfamide - pharmacology Medical sciences Pharmacology. Drug treatments Phosphoramide Mustards - pharmacology |
| title | Effects of alkylating metabolites of ifosfamide and its bromo analogues on DNA of HeLa cells |
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