Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells
The in vitro cytotoxicity and mechanism of action of cyclophosphamide (CP) were studied in a dual cell culture system, using rat hepatocytes and K562 human chronic myeloid leukemia cells. Cytotoxicity and DNA damage were measurable in K562 cells using CP concentrations that are clinically attainable...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1986-10, Vol.46 (10), p.5029-5034 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | CROOK, T. R SOUHAMI, R. L MCLEAN, A. E. M |
| description | The in vitro cytotoxicity and mechanism of action of cyclophosphamide (CP) were studied in a dual cell culture system, using rat hepatocytes and K562 human chronic myeloid leukemia cells. Cytotoxicity and DNA damage were measurable in K562 cells using CP concentrations that are clinically attainable. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent DNA interstrand cross-links, DNA-protein cross-links, and DNA single strand breaks in K562 cells following a 1-h exposure to cyclophosphamide activated by hepatocytes. Hepatocyte-activated CP was 3 to 4 times more potent than phosphoramide mustard with regard to cytotoxicity and induction of DNA interstrand cross-links. Exposure to phosphoramide mustard did not produce single strand breaks, but exposure of K562 cells to acrolein resulted in substantial levels of single strand breaks. The demonstration of acrolein-induced single strand breaks following exposure to activated CP is a novel finding and suggests that acrolein may have a role in the cytotoxicity of CP. |
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R ; SOUHAMI, R. L ; MCLEAN, A. E. M</creator><creatorcontrib>CROOK, T. R ; SOUHAMI, R. L ; MCLEAN, A. E. M</creatorcontrib><description>The in vitro cytotoxicity and mechanism of action of cyclophosphamide (CP) were studied in a dual cell culture system, using rat hepatocytes and K562 human chronic myeloid leukemia cells. Cytotoxicity and DNA damage were measurable in K562 cells using CP concentrations that are clinically attainable. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent DNA interstrand cross-links, DNA-protein cross-links, and DNA single strand breaks in K562 cells following a 1-h exposure to cyclophosphamide activated by hepatocytes. Hepatocyte-activated CP was 3 to 4 times more potent than phosphoramide mustard with regard to cytotoxicity and induction of DNA interstrand cross-links. Exposure to phosphoramide mustard did not produce single strand breaks, but exposure of K562 cells to acrolein resulted in substantial levels of single strand breaks. The demonstration of acrolein-induced single strand breaks following exposure to activated CP is a novel finding and suggests that acrolein may have a role in the cytotoxicity of CP.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 3463409</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Acrolein - pharmacology ; Aldehydes - pharmacology ; Alkylation ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Biotransformation ; Cell Line ; Cell Survival - drug effects ; Chemotherapy ; Cyclophosphamide - metabolism ; Cyclophosphamide - pharmacology ; DNA - drug effects ; DNA - metabolism ; DNA Damage ; Humans ; In Vitro Techniques ; Leukemia, Myeloid - metabolism ; Leukemia, Myeloid - pathology ; Liver - metabolism ; Male ; Medical sciences ; Pharmacology. Drug treatments ; Phosphoramide Mustards - pharmacology ; Rats ; Rats, Inbred Strains</subject><ispartof>Cancer research (Chicago, Ill.), 1986-10, Vol.46 (10), p.5029-5034</ispartof><rights>1987 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=8142517$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3463409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CROOK, T. R</creatorcontrib><creatorcontrib>SOUHAMI, R. L</creatorcontrib><creatorcontrib>MCLEAN, A. E. M</creatorcontrib><title>Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The in vitro cytotoxicity and mechanism of action of cyclophosphamide (CP) were studied in a dual cell culture system, using rat hepatocytes and K562 human chronic myeloid leukemia cells. Cytotoxicity and DNA damage were measurable in K562 cells using CP concentrations that are clinically attainable. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent DNA interstrand cross-links, DNA-protein cross-links, and DNA single strand breaks in K562 cells following a 1-h exposure to cyclophosphamide activated by hepatocytes. Hepatocyte-activated CP was 3 to 4 times more potent than phosphoramide mustard with regard to cytotoxicity and induction of DNA interstrand cross-links. Exposure to phosphoramide mustard did not produce single strand breaks, but exposure of K562 cells to acrolein resulted in substantial levels of single strand breaks. The demonstration of acrolein-induced single strand breaks following exposure to activated CP is a novel finding and suggests that acrolein may have a role in the cytotoxicity of CP.</description><subject>Acrolein - pharmacology</subject><subject>Aldehydes - pharmacology</subject><subject>Alkylation</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Chemotherapy</subject><subject>Cyclophosphamide - metabolism</subject><subject>Cyclophosphamide - pharmacology</subject><subject>DNA - drug effects</subject><subject>DNA - metabolism</subject><subject>DNA Damage</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Leukemia, Myeloid - metabolism</subject><subject>Leukemia, Myeloid - pathology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphoramide Mustards - pharmacology</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1986</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kEtLxDAQx4Mo67r6EYQcPFpImkfT47I-YdGLnpc0ndi46YMmFXv3gxt18TTz4_-AmSO0pIKprOBcHKMlIURlghf5KToL4T2hoEQs0IJxyTgpl-hrM8c-9p_OuDhf45unNTZjH0LmXbd33ds11l2NQ9o84BDHH6pG0PuAXVdPBhLOWJvoPnRMYGbj-6Hpw9Do1tXwG9ep0oPrUgQ3U6s77GHaQ-s0NuB9OEcnVvsAF4e5Qq93ty-bh2z7fP-4WW-zJpdlzCTn1lJBakMNKGm1JSWVTFXAuQKR87wSFZGlMiVRiucAFS8KliySWkEYW6HLv95hqlqod8PoWj3Ou8M3kn510HUw2tt0rXHh36YozwUt2DdHD2qX</recordid><startdate>19861001</startdate><enddate>19861001</enddate><creator>CROOK, T. R</creator><creator>SOUHAMI, R. L</creator><creator>MCLEAN, A. E. M</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>19861001</creationdate><title>Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells</title><author>CROOK, T. R ; SOUHAMI, R. L ; MCLEAN, A. E. M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-644ff150dc1ce86faf091638be448e5242b5b0698c908842eeb477316361f5033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1986</creationdate><topic>Acrolein - pharmacology</topic><topic>Aldehydes - pharmacology</topic><topic>Alkylation</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Cell Line</topic><topic>Cell Survival - drug effects</topic><topic>Chemotherapy</topic><topic>Cyclophosphamide - metabolism</topic><topic>Cyclophosphamide - pharmacology</topic><topic>DNA - drug effects</topic><topic>DNA - metabolism</topic><topic>DNA Damage</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Leukemia, Myeloid - metabolism</topic><topic>Leukemia, Myeloid - pathology</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphoramide Mustards - pharmacology</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CROOK, T. R</creatorcontrib><creatorcontrib>SOUHAMI, R. L</creatorcontrib><creatorcontrib>MCLEAN, A. E. M</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>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CROOK, T. R</au><au>SOUHAMI, R. L</au><au>MCLEAN, A. E. M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1986-10-01</date><risdate>1986</risdate><volume>46</volume><issue>10</issue><spage>5029</spage><epage>5034</epage><pages>5029-5034</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The in vitro cytotoxicity and mechanism of action of cyclophosphamide (CP) were studied in a dual cell culture system, using rat hepatocytes and K562 human chronic myeloid leukemia cells. Cytotoxicity and DNA damage were measurable in K562 cells using CP concentrations that are clinically attainable. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-dependent DNA interstrand cross-links, DNA-protein cross-links, and DNA single strand breaks in K562 cells following a 1-h exposure to cyclophosphamide activated by hepatocytes. Hepatocyte-activated CP was 3 to 4 times more potent than phosphoramide mustard with regard to cytotoxicity and induction of DNA interstrand cross-links. Exposure to phosphoramide mustard did not produce single strand breaks, but exposure of K562 cells to acrolein resulted in substantial levels of single strand breaks. The demonstration of acrolein-induced single strand breaks following exposure to activated CP is a novel finding and suggests that acrolein may have a role in the cytotoxicity of CP.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>3463409</pmid><tpages>6</tpages></addata></record> |
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| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 1986-10, Vol.46 (10), p.5029-5034 |
| issn | 0008-5472 1538-7445 |
| language | eng |
| recordid | cdi_pubmed_primary_3463409 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Acrolein - pharmacology Aldehydes - pharmacology Alkylation Animals Antineoplastic agents Biological and medical sciences Biotransformation Cell Line Cell Survival - drug effects Chemotherapy Cyclophosphamide - metabolism Cyclophosphamide - pharmacology DNA - drug effects DNA - metabolism DNA Damage Humans In Vitro Techniques Leukemia, Myeloid - metabolism Leukemia, Myeloid - pathology Liver - metabolism Male Medical sciences Pharmacology. Drug treatments Phosphoramide Mustards - pharmacology Rats Rats, Inbred Strains |
| title | Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells |
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