Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells
The effect of VP-16-213 on cellular DNA was studied by following the sedimentation profiles of radioactive DNA in HeLa cells on alkaline sucrose gradients. In VP-16-213 treated cells, high-molecular-weight DNA is converted to a lower molecular-weight form in a dose-dependent, temperature-dependent r...
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| Veröffentlicht in: | Biochemistry (Easton) 1976-12, Vol.15 (25), p.5443-5448 |
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| container_title | Biochemistry (Easton) |
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| creator | Loike, John D Horwitz, Susan B |
| description | The effect of VP-16-213 on cellular DNA was studied by following the sedimentation profiles of radioactive DNA in HeLa cells on alkaline sucrose gradients. In VP-16-213 treated cells, high-molecular-weight DNA is converted to a lower molecular-weight form in a dose-dependent, temperature-dependent reaction. The effect of VP-16-213 on cellular DNA is reversed after the drug has been removed from the growth medium for 150 min. These results suggest that VP-16-213 induces single-stranded breaks in DNA in HeLa cells and that HeLa cells can repair these breaks within 150 min. The nonglucoside derivative of VP-16-213, 4'-demethylepipodophyllotoxin, also induces the cleavage of cellular DNA but podophyllotoxin has no effect on DNA. A structure-activity relationship study, in which the effects of various VP-16-213 and podophyllotoxin congeners were tested for their ability to cleave cellular DNA,revealed that an hydroxyl group at the C-4' position is required for activity and that the configuration of the C-4 carbon influences the activity of a congener. These results may offer insights into the mechanism of action of VP-16-213 as an antitumor agent. |
| doi_str_mv | 10.1021/bi00670a004 |
| format | Article |
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In VP-16-213 treated cells, high-molecular-weight DNA is converted to a lower molecular-weight form in a dose-dependent, temperature-dependent reaction. The effect of VP-16-213 on cellular DNA is reversed after the drug has been removed from the growth medium for 150 min. These results suggest that VP-16-213 induces single-stranded breaks in DNA in HeLa cells and that HeLa cells can repair these breaks within 150 min. The nonglucoside derivative of VP-16-213, 4'-demethylepipodophyllotoxin, also induces the cleavage of cellular DNA but podophyllotoxin has no effect on DNA. A structure-activity relationship study, in which the effects of various VP-16-213 and podophyllotoxin congeners were tested for their ability to cleave cellular DNA,revealed that an hydroxyl group at the C-4' position is required for activity and that the configuration of the C-4 carbon influences the activity of a congener. These results may offer insights into the mechanism of action of VP-16-213 as an antitumor agent.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi00670a004</identifier><identifier>PMID: 999819</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adenoviruses, Human ; DNA - metabolism ; DNA, Viral - metabolism ; Dose-Response Relationship, Drug ; Etoposide - pharmacology ; HeLa Cells - drug effects ; HeLa Cells - metabolism ; Molecular Weight ; Podophyllotoxin - analogs & derivatives ; Podophyllotoxin - pharmacology ; Temperature</subject><ispartof>Biochemistry (Easton), 1976-12, Vol.15 (25), p.5443-5448</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a419t-1c00ad180ea2203bd446431ced0e1788ffaa8d7bb5489a6447ff8e2949d77e73</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/bi00670a004$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bi00670a004$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2769,27085,27933,27934,56747,56797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/999819$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Loike, John D</creatorcontrib><creatorcontrib>Horwitz, Susan B</creatorcontrib><title>Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>The effect of VP-16-213 on cellular DNA was studied by following the sedimentation profiles of radioactive DNA in HeLa cells on alkaline sucrose gradients. In VP-16-213 treated cells, high-molecular-weight DNA is converted to a lower molecular-weight form in a dose-dependent, temperature-dependent reaction. The effect of VP-16-213 on cellular DNA is reversed after the drug has been removed from the growth medium for 150 min. These results suggest that VP-16-213 induces single-stranded breaks in DNA in HeLa cells and that HeLa cells can repair these breaks within 150 min. The nonglucoside derivative of VP-16-213, 4'-demethylepipodophyllotoxin, also induces the cleavage of cellular DNA but podophyllotoxin has no effect on DNA. A structure-activity relationship study, in which the effects of various VP-16-213 and podophyllotoxin congeners were tested for their ability to cleave cellular DNA,revealed that an hydroxyl group at the C-4' position is required for activity and that the configuration of the C-4 carbon influences the activity of a congener. These results may offer insights into the mechanism of action of VP-16-213 as an antitumor agent.</description><subject>Adenoviruses, Human</subject><subject>DNA - metabolism</subject><subject>DNA, Viral - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Etoposide - pharmacology</subject><subject>HeLa Cells - drug effects</subject><subject>HeLa Cells - metabolism</subject><subject>Molecular Weight</subject><subject>Podophyllotoxin - analogs & derivatives</subject><subject>Podophyllotoxin - pharmacology</subject><subject>Temperature</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1976</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0M9LwzAUB_Ag_prTk1cPPelBqi9t2iTHsU03HDpwKHgJr22inds6kxb0vzejY3jwFB7fD--FLyHnFG4oRPQ2KwFSDgjA9kiHJhGETMpkn3TAB2EkUzgmJ87N_ciAsyNyKKUUVHbIeGiMzuugMsHLNKQe0zioVkH9oYNyVVvM9WLRLNAGhX63WGBd-tTrwWPPg2CkJxhsjDslBwYXTp9t3y6Z3Q1n_VE4ebof93uTEBmVdUhzACyoAI1RBHFWMJaymOa6AE25EMYgioJnWcKExJQxbozQkWSy4FzzuEsu27VrW3012tVqWbrNB3Clq8YpEadpLFLq4XULc1s5Z7VRa1su0f4oCmpTm_pTm9cX27VNttTFzrY9-Ths49LV-nuXov1UKY95ombTZ_Xaf5vJwUOiYu-vWo-5U_OqsStfyb-HfwHqk4Av</recordid><startdate>19761201</startdate><enddate>19761201</enddate><creator>Loike, John D</creator><creator>Horwitz, Susan B</creator><general>American Chemical Society</general><scope>BSCLL</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>19761201</creationdate><title>Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells</title><author>Loike, John D ; Horwitz, Susan B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a419t-1c00ad180ea2203bd446431ced0e1788ffaa8d7bb5489a6447ff8e2949d77e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1976</creationdate><topic>Adenoviruses, Human</topic><topic>DNA - metabolism</topic><topic>DNA, Viral - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Etoposide - pharmacology</topic><topic>HeLa Cells - drug effects</topic><topic>HeLa Cells - metabolism</topic><topic>Molecular Weight</topic><topic>Podophyllotoxin - analogs & derivatives</topic><topic>Podophyllotoxin - pharmacology</topic><topic>Temperature</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Loike, John D</creatorcontrib><creatorcontrib>Horwitz, Susan B</creatorcontrib><collection>Istex</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>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Loike, John D</au><au>Horwitz, Susan B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>1976-12-01</date><risdate>1976</risdate><volume>15</volume><issue>25</issue><spage>5443</spage><epage>5448</epage><pages>5443-5448</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>The effect of VP-16-213 on cellular DNA was studied by following the sedimentation profiles of radioactive DNA in HeLa cells on alkaline sucrose gradients. In VP-16-213 treated cells, high-molecular-weight DNA is converted to a lower molecular-weight form in a dose-dependent, temperature-dependent reaction. The effect of VP-16-213 on cellular DNA is reversed after the drug has been removed from the growth medium for 150 min. These results suggest that VP-16-213 induces single-stranded breaks in DNA in HeLa cells and that HeLa cells can repair these breaks within 150 min. The nonglucoside derivative of VP-16-213, 4'-demethylepipodophyllotoxin, also induces the cleavage of cellular DNA but podophyllotoxin has no effect on DNA. A structure-activity relationship study, in which the effects of various VP-16-213 and podophyllotoxin congeners were tested for their ability to cleave cellular DNA,revealed that an hydroxyl group at the C-4' position is required for activity and that the configuration of the C-4 carbon influences the activity of a congener. These results may offer insights into the mechanism of action of VP-16-213 as an antitumor agent.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>999819</pmid><doi>10.1021/bi00670a004</doi><tpages>6</tpages></addata></record> |
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| ispartof | Biochemistry (Easton), 1976-12, Vol.15 (25), p.5443-5448 |
| issn | 0006-2960 1520-4995 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Adenoviruses, Human DNA - metabolism DNA, Viral - metabolism Dose-Response Relationship, Drug Etoposide - pharmacology HeLa Cells - drug effects HeLa Cells - metabolism Molecular Weight Podophyllotoxin - analogs & derivatives Podophyllotoxin - pharmacology Temperature |
| title | Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells |
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