Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models
The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2008-04, Vol.320 (5873), p.226-230 |
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| creator | Burdelya, Lyudmila G Krivokrysenko, Vadim I Tallant, Thomas C Strom, Evguenia Gleiberman, Anatoly S Gupta, Damodar Kurnasov, Oleg V Fort, Farrel L Osterman, Andrei L DiDonato, Joseph A Feinstein, Elena Gudkov, Andrei V |
| description | The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-κB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies. |
| doi_str_mv | 10.1126/science.1154986 |
| format | Article |
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Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-κB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1154986</identifier><identifier>PMID: 18403709</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Agonists ; Amino Acid Sequence ; Animals ; Antineoplastic agents ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - radiation effects ; Biological and medical sciences ; Cellular biology ; Chemotherapy, Adjuvant ; Crypts ; Endothelial cells ; Flagellin - chemistry ; Flagellin - pharmacology ; Gamma Rays ; General aspects ; Hematopoietic System - drug effects ; Hematopoietic System - radiation effects ; Intestine, Small - cytology ; Intestine, Small - drug effects ; Intestine, Small - radiation effects ; Irradiation ; Macaca mulatta ; Medical sciences ; Mice ; Mice, Inbred ICR ; Molecular Sequence Data ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - radiotherapy ; NF-kappa B - metabolism ; Peptides - administration & dosage ; Peptides - chemistry ; Peptides - pharmacology ; Peptides - toxicity ; Pharmacology. Drug treatments ; Primates ; Radiation ; Radiation Dosage ; Radiation Injuries, Experimental - prevention & control ; Radiation protection ; Radiation Tolerance - drug effects ; Radiation-Protective Agents - administration & dosage ; Radiation-Protective Agents - chemistry ; Radiation-Protective Agents - pharmacology ; Radiation-Protective Agents - toxicity ; Radiotherapy ; Rodents ; Salmonella ; Salmonella enterica ; Signal Transduction ; Small intestine ; Stem cells ; Toll-Like Receptor 5 - agonists ; Toll-Like Receptor 5 - metabolism ; Toxicity ; Tumors ; Whole-Body Irradiation</subject><ispartof>Science (American Association for the Advancement of Science), 2008-04, Vol.320 (5873), p.226-230</ispartof><rights>Copyright 2008 American Association for the Advancement of Science</rights><rights>2008 INIST-CNRS</rights><rights>Copyright © 2008, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c621t-592e29b466eb9c7f9ffc8f4381f2650d7507f9d4b4d316b9e01860b013f903f93</citedby><cites>FETCH-LOGICAL-c621t-592e29b466eb9c7f9ffc8f4381f2650d7507f9d4b4d316b9e01860b013f903f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/20054988$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/20054988$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,776,780,799,881,2871,2872,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20281874$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18403709$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Burdelya, Lyudmila G</creatorcontrib><creatorcontrib>Krivokrysenko, Vadim I</creatorcontrib><creatorcontrib>Tallant, Thomas C</creatorcontrib><creatorcontrib>Strom, Evguenia</creatorcontrib><creatorcontrib>Gleiberman, Anatoly S</creatorcontrib><creatorcontrib>Gupta, Damodar</creatorcontrib><creatorcontrib>Kurnasov, Oleg V</creatorcontrib><creatorcontrib>Fort, Farrel L</creatorcontrib><creatorcontrib>Osterman, Andrei L</creatorcontrib><creatorcontrib>DiDonato, Joseph A</creatorcontrib><creatorcontrib>Feinstein, Elena</creatorcontrib><creatorcontrib>Gudkov, Andrei V</creatorcontrib><title>Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-κB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.</description><subject>Agonists</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - radiation effects</subject><subject>Biological and medical sciences</subject><subject>Cellular biology</subject><subject>Chemotherapy, Adjuvant</subject><subject>Crypts</subject><subject>Endothelial cells</subject><subject>Flagellin - chemistry</subject><subject>Flagellin - pharmacology</subject><subject>Gamma Rays</subject><subject>General aspects</subject><subject>Hematopoietic System - drug effects</subject><subject>Hematopoietic System - radiation effects</subject><subject>Intestine, Small - cytology</subject><subject>Intestine, Small - drug effects</subject><subject>Intestine, Small - radiation effects</subject><subject>Irradiation</subject><subject>Macaca mulatta</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Molecular Sequence Data</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - radiotherapy</subject><subject>NF-kappa B - metabolism</subject><subject>Peptides - administration & dosage</subject><subject>Peptides - chemistry</subject><subject>Peptides - pharmacology</subject><subject>Peptides - toxicity</subject><subject>Pharmacology. Drug treatments</subject><subject>Primates</subject><subject>Radiation</subject><subject>Radiation Dosage</subject><subject>Radiation Injuries, Experimental - prevention & control</subject><subject>Radiation protection</subject><subject>Radiation Tolerance - drug effects</subject><subject>Radiation-Protective Agents - administration & dosage</subject><subject>Radiation-Protective Agents - chemistry</subject><subject>Radiation-Protective Agents - pharmacology</subject><subject>Radiation-Protective Agents - toxicity</subject><subject>Radiotherapy</subject><subject>Rodents</subject><subject>Salmonella</subject><subject>Salmonella enterica</subject><subject>Signal Transduction</subject><subject>Small intestine</subject><subject>Stem cells</subject><subject>Toll-Like Receptor 5 - agonists</subject><subject>Toll-Like Receptor 5 - metabolism</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Whole-Body Irradiation</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9rFDEUx4Modq2ePalB0NvYl2Qmk1yEpagVVpTagreQybysWWcnazJb6H9vlh1q9RAeed9P3o98CXnO4B1jXJ5lF3B0WC5NrZV8QBYMdFNpDuIhWQAIWSlomxPyJOcNQNG0eExOmKpBtKAX5MdyHceQJxo9vYrDUK3CL6SX6HA3xUQbemEzvbR9iLsUJ3RTuEG6PIQw3dIw0i9xn5HasaffUtjaCUumxyE_JY-8HTI-m-Mpuf744er8olp9_fT5fLmqnORsqhrNkeuulhI77VqvvXfK10Ixz2UDfdtASfZ1V_eCyU4jMCWhAya8hnLEKXl_rLvbd1vsHY5TsoPZHYZJtybaYP5VxvDTrOONqQXnWjSlwNu5QIq_95gnsw3Z4TDYEctuhoNSrYAD-Po_cBP3aSzLGc5Eo6USbYHOjpBLMeeE_m4SBuZgmZktM7Nl5cXL-wv85WePCvBmBmx2dvDJji7kO44DV0y1deFeHLlNLtbd0-HQSBX91VH3Nhq7TqXG9XdefhLKhqWTEn8AAq-ytA</recordid><startdate>20080411</startdate><enddate>20080411</enddate><creator>Burdelya, Lyudmila G</creator><creator>Krivokrysenko, Vadim I</creator><creator>Tallant, Thomas C</creator><creator>Strom, Evguenia</creator><creator>Gleiberman, Anatoly S</creator><creator>Gupta, Damodar</creator><creator>Kurnasov, Oleg V</creator><creator>Fort, Farrel L</creator><creator>Osterman, Andrei L</creator><creator>DiDonato, Joseph A</creator><creator>Feinstein, Elena</creator><creator>Gudkov, Andrei V</creator><general>American Association for the Advancement of Science</general><general>The American Association for the Advancement of Science</general><scope>FBQ</scope><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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7T5</scope><scope>5PM</scope></search><sort><creationdate>20080411</creationdate><title>Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models</title><author>Burdelya, Lyudmila G ; Krivokrysenko, Vadim I ; Tallant, Thomas C ; Strom, Evguenia ; Gleiberman, Anatoly S ; Gupta, Damodar ; Kurnasov, Oleg V ; Fort, Farrel L ; Osterman, Andrei L ; DiDonato, Joseph A ; Feinstein, Elena ; Gudkov, Andrei V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c621t-592e29b466eb9c7f9ffc8f4381f2650d7507f9d4b4d316b9e01860b013f903f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Agonists</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - radiation effects</topic><topic>Biological and medical sciences</topic><topic>Cellular biology</topic><topic>Chemotherapy, Adjuvant</topic><topic>Crypts</topic><topic>Endothelial cells</topic><topic>Flagellin - chemistry</topic><topic>Flagellin - pharmacology</topic><topic>Gamma Rays</topic><topic>General aspects</topic><topic>Hematopoietic System - drug effects</topic><topic>Hematopoietic System - radiation effects</topic><topic>Intestine, Small - cytology</topic><topic>Intestine, Small - drug effects</topic><topic>Intestine, Small - radiation effects</topic><topic>Irradiation</topic><topic>Macaca mulatta</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Molecular Sequence Data</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - radiotherapy</topic><topic>NF-kappa B - metabolism</topic><topic>Peptides - administration & dosage</topic><topic>Peptides - chemistry</topic><topic>Peptides - pharmacology</topic><topic>Peptides - toxicity</topic><topic>Pharmacology. Drug treatments</topic><topic>Primates</topic><topic>Radiation</topic><topic>Radiation Dosage</topic><topic>Radiation Injuries, Experimental - prevention & control</topic><topic>Radiation protection</topic><topic>Radiation Tolerance - drug effects</topic><topic>Radiation-Protective Agents - administration & dosage</topic><topic>Radiation-Protective Agents - chemistry</topic><topic>Radiation-Protective Agents - pharmacology</topic><topic>Radiation-Protective Agents - toxicity</topic><topic>Radiotherapy</topic><topic>Rodents</topic><topic>Salmonella</topic><topic>Salmonella enterica</topic><topic>Signal Transduction</topic><topic>Small intestine</topic><topic>Stem cells</topic><topic>Toll-Like Receptor 5 - agonists</topic><topic>Toll-Like Receptor 5 - metabolism</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Whole-Body Irradiation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Burdelya, Lyudmila 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Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-κB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. 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| ispartof | Science (American Association for the Advancement of Science), 2008-04, Vol.320 (5873), p.226-230 |
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| source | American Association for the Advancement of Science; Jstor Complete Legacy; MEDLINE |
| subjects | Agonists Amino Acid Sequence Animals Antineoplastic agents Apoptosis Apoptosis - drug effects Apoptosis - radiation effects Biological and medical sciences Cellular biology Chemotherapy, Adjuvant Crypts Endothelial cells Flagellin - chemistry Flagellin - pharmacology Gamma Rays General aspects Hematopoietic System - drug effects Hematopoietic System - radiation effects Intestine, Small - cytology Intestine, Small - drug effects Intestine, Small - radiation effects Irradiation Macaca mulatta Medical sciences Mice Mice, Inbred ICR Molecular Sequence Data Neoplasms, Experimental - drug therapy Neoplasms, Experimental - radiotherapy NF-kappa B - metabolism Peptides - administration & dosage Peptides - chemistry Peptides - pharmacology Peptides - toxicity Pharmacology. Drug treatments Primates Radiation Radiation Dosage Radiation Injuries, Experimental - prevention & control Radiation protection Radiation Tolerance - drug effects Radiation-Protective Agents - administration & dosage Radiation-Protective Agents - chemistry Radiation-Protective Agents - pharmacology Radiation-Protective Agents - toxicity Radiotherapy Rodents Salmonella Salmonella enterica Signal Transduction Small intestine Stem cells Toll-Like Receptor 5 - agonists Toll-Like Receptor 5 - metabolism Toxicity Tumors Whole-Body Irradiation |
| title | Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models |
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