NLA-1 : A 2-nitroimidazole radiosensitizer targeted to DNA by intercalation
Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DN...
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| Veröffentlicht in: | International journal of radiation oncology, biology, physics biology, physics, 1992, Vol.22 (3), p.553-556 |
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| container_title | International journal of radiation oncology, biology, physics |
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| creator | Denny, William A. Roberts, Peter B. Anderson, Robert F. Martin Brown, J. Wilson, William R. |
| description | Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is ≈1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (≈11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C
1.6) of 9 μM. The mean intracellular concentration at the C
1.6 is 400 μM, on which basis its potency is about twice that of MISO. The
in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C
1.6) of NLA-1 is ≈ 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors
in vivo at the maximum tolerated dose (MTD) of 100 μmol·kg
−1. |
| doi_str_mv | 10.1016/0360-3016(92)90874-H |
| format | Article |
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1.6) of 9 μM. The mean intracellular concentration at the C
1.6 is 400 μM, on which basis its potency is about twice that of MISO. The
in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C
1.6) of NLA-1 is ≈ 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors
in vivo at the maximum tolerated dose (MTD) of 100 μmol·kg
−1.</description><identifier>ISSN: 0360-3016</identifier><identifier>EISSN: 1879-355X</identifier><identifier>DOI: 10.1016/0360-3016(92)90874-H</identifier><identifier>PMID: 1735695</identifier><identifier>CODEN: IOBPD3</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>2-nitroimidazole ; Acridine ; Aminoacridines - metabolism ; Aminoacridines - pharmacology ; Aminoacridines - therapeutic use ; Animals ; Biological and medical sciences ; Cell Hypoxia - drug effects ; Cell Hypoxia - physiology ; Cell Hypoxia - radiation effects ; Cell Line ; Combined Modality Therapy ; DNA - metabolism ; DNA intercalation ; DNA, Neoplasm - metabolism ; EMT6 ; HPLC ; Intercalating Agents - metabolism ; Intercalating Agents - pharmacology ; Intercalating Agents - therapeutic use ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Misonidazole ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - radiotherapy ; Nitroimidazoles - metabolism ; Nitroimidazoles - pharmacology ; Nitroimidazoles - therapeutic use ; NLA-1 ; Pimonidazole ; Radiation therapy and radiosensitizing agent ; Radiation-Sensitizing Agents - metabolism ; Radiation-Sensitizing Agents - pharmacology ; Radiation-Sensitizing Agents - therapeutic use ; SCCVII ; Treatment with physical agents ; Treatment. General aspects ; Tumors</subject><ispartof>International journal of radiation oncology, biology, physics, 1992, Vol.22 (3), p.553-556</ispartof><rights>1992</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c432t-a1dacaff17a84625bd616bfec018b6ac9ab5c2c24a9ead8044766763857983</citedby><cites>FETCH-LOGICAL-c432t-a1dacaff17a84625bd616bfec018b6ac9ab5c2c24a9ead8044766763857983</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/036030169290874H$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>309,310,314,776,780,785,786,3537,4010,4036,4037,23909,23910,25118,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4437134$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1735695$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Denny, William A.</creatorcontrib><creatorcontrib>Roberts, Peter B.</creatorcontrib><creatorcontrib>Anderson, Robert F.</creatorcontrib><creatorcontrib>Martin Brown, J.</creatorcontrib><creatorcontrib>Wilson, William R.</creatorcontrib><title>NLA-1 : A 2-nitroimidazole radiosensitizer targeted to DNA by intercalation</title><title>International journal of radiation oncology, biology, physics</title><addtitle>Int J Radiat Oncol Biol Phys</addtitle><description>Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is ≈1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (≈11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C
1.6) of 9 μM. The mean intracellular concentration at the C
1.6 is 400 μM, on which basis its potency is about twice that of MISO. The
in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C
1.6) of NLA-1 is ≈ 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors
in vivo at the maximum tolerated dose (MTD) of 100 μmol·kg
−1.</description><subject>2-nitroimidazole</subject><subject>Acridine</subject><subject>Aminoacridines - metabolism</subject><subject>Aminoacridines - pharmacology</subject><subject>Aminoacridines - therapeutic use</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Hypoxia - drug effects</subject><subject>Cell Hypoxia - physiology</subject><subject>Cell Hypoxia - radiation effects</subject><subject>Cell Line</subject><subject>Combined Modality Therapy</subject><subject>DNA - metabolism</subject><subject>DNA intercalation</subject><subject>DNA, Neoplasm - metabolism</subject><subject>EMT6</subject><subject>HPLC</subject><subject>Intercalating Agents - metabolism</subject><subject>Intercalating Agents - pharmacology</subject><subject>Intercalating Agents - therapeutic use</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C3H</subject><subject>Misonidazole</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - radiotherapy</subject><subject>Nitroimidazoles - metabolism</subject><subject>Nitroimidazoles - pharmacology</subject><subject>Nitroimidazoles - therapeutic use</subject><subject>NLA-1</subject><subject>Pimonidazole</subject><subject>Radiation therapy and radiosensitizing agent</subject><subject>Radiation-Sensitizing Agents - metabolism</subject><subject>Radiation-Sensitizing Agents - pharmacology</subject><subject>Radiation-Sensitizing Agents - therapeutic use</subject><subject>SCCVII</subject><subject>Treatment with physical agents</subject><subject>Treatment. General aspects</subject><subject>Tumors</subject><issn>0360-3016</issn><issn>1879-355X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kFFLHDEQx4O02Kv6DSzkoUh92JpsssnGB-GwtVc8LBQffAuzyWxJ2dtokhP007vnHfatTzMwv_8w8yPkmLOvnHF1xoRilZi6L6Y-NazVslrskRlvtalE09y9I7M35AP5mPNfxhjnWu6Tfa5Fo0wzI9c3y3nF6Tmd07oaQ0kxrIKH5zggTeBDzDjmUMIzJlog_cGCnpZIv93MafdEw1gwORighDgekvc9DBmPdvWA_L76fnu5qJa_fvy8nC8rJ0VdKuAeHPQ919BKVTedV1x1PTrG206BM9A1rna1BIPgWyalVkor0TbatOKAnGyX3qf4sMZc7Cpkh8MAI8Z1trpumdDaTKDcgi7FnBP29j6FFaQny5ndCLQbO3Zjx5ravgq0iyn2abd_3a3Q_wttjU3zz7s55OnxPsHoQn7DpBSaCzlhF1sMJxGPAZPNLuDo0IeErlgfw__veAEJMotO</recordid><startdate>1992</startdate><enddate>1992</enddate><creator>Denny, William A.</creator><creator>Roberts, Peter B.</creator><creator>Anderson, Robert F.</creator><creator>Martin Brown, J.</creator><creator>Wilson, William R.</creator><general>Elsevier Inc</general><general>Elsevier</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>1992</creationdate><title>NLA-1 : A 2-nitroimidazole radiosensitizer targeted to DNA by intercalation</title><author>Denny, William A. ; Roberts, Peter B. ; Anderson, Robert F. ; Martin Brown, J. ; Wilson, William R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c432t-a1dacaff17a84625bd616bfec018b6ac9ab5c2c24a9ead8044766763857983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>2-nitroimidazole</topic><topic>Acridine</topic><topic>Aminoacridines - metabolism</topic><topic>Aminoacridines - pharmacology</topic><topic>Aminoacridines - therapeutic use</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Hypoxia - drug effects</topic><topic>Cell Hypoxia - physiology</topic><topic>Cell Hypoxia - radiation effects</topic><topic>Cell Line</topic><topic>Combined Modality Therapy</topic><topic>DNA - metabolism</topic><topic>DNA intercalation</topic><topic>DNA, Neoplasm - metabolism</topic><topic>EMT6</topic><topic>HPLC</topic><topic>Intercalating Agents - metabolism</topic><topic>Intercalating Agents - pharmacology</topic><topic>Intercalating Agents - therapeutic use</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C3H</topic><topic>Misonidazole</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - radiotherapy</topic><topic>Nitroimidazoles - metabolism</topic><topic>Nitroimidazoles - pharmacology</topic><topic>Nitroimidazoles - therapeutic use</topic><topic>NLA-1</topic><topic>Pimonidazole</topic><topic>Radiation therapy and radiosensitizing agent</topic><topic>Radiation-Sensitizing Agents - metabolism</topic><topic>Radiation-Sensitizing Agents - pharmacology</topic><topic>Radiation-Sensitizing Agents - therapeutic use</topic><topic>SCCVII</topic><topic>Treatment with physical agents</topic><topic>Treatment. General aspects</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Denny, William A.</creatorcontrib><creatorcontrib>Roberts, Peter B.</creatorcontrib><creatorcontrib>Anderson, Robert F.</creatorcontrib><creatorcontrib>Martin Brown, J.</creatorcontrib><creatorcontrib>Wilson, William R.</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>International journal of radiation oncology, biology, physics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Denny, William A.</au><au>Roberts, Peter B.</au><au>Anderson, Robert F.</au><au>Martin Brown, J.</au><au>Wilson, William R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NLA-1 : A 2-nitroimidazole radiosensitizer targeted to DNA by intercalation</atitle><jtitle>International journal of radiation oncology, biology, physics</jtitle><addtitle>Int J Radiat Oncol Biol Phys</addtitle><date>1992</date><risdate>1992</risdate><volume>22</volume><issue>3</issue><spage>553</spage><epage>556</epage><pages>553-556</pages><issn>0360-3016</issn><eissn>1879-355X</eissn><coden>IOBPD3</coden><abstract>Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is ≈1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (≈11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C
1.6) of 9 μM. The mean intracellular concentration at the C
1.6 is 400 μM, on which basis its potency is about twice that of MISO. The
in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C
1.6) of NLA-1 is ≈ 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors
in vivo at the maximum tolerated dose (MTD) of 100 μmol·kg
−1.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>1735695</pmid><doi>10.1016/0360-3016(92)90874-H</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0360-3016 |
| ispartof | International journal of radiation oncology, biology, physics, 1992, Vol.22 (3), p.553-556 |
| issn | 0360-3016 1879-355X |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 2-nitroimidazole Acridine Aminoacridines - metabolism Aminoacridines - pharmacology Aminoacridines - therapeutic use Animals Biological and medical sciences Cell Hypoxia - drug effects Cell Hypoxia - physiology Cell Hypoxia - radiation effects Cell Line Combined Modality Therapy DNA - metabolism DNA intercalation DNA, Neoplasm - metabolism EMT6 HPLC Intercalating Agents - metabolism Intercalating Agents - pharmacology Intercalating Agents - therapeutic use Medical sciences Mice Mice, Inbred BALB C Mice, Inbred C3H Misonidazole Neoplasms, Experimental - drug therapy Neoplasms, Experimental - radiotherapy Nitroimidazoles - metabolism Nitroimidazoles - pharmacology Nitroimidazoles - therapeutic use NLA-1 Pimonidazole Radiation therapy and radiosensitizing agent Radiation-Sensitizing Agents - metabolism Radiation-Sensitizing Agents - pharmacology Radiation-Sensitizing Agents - therapeutic use SCCVII Treatment with physical agents Treatment. General aspects Tumors |
| title | NLA-1 : A 2-nitroimidazole radiosensitizer targeted to DNA by intercalation |
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