RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients

Background Several reports describe the importance of the chaperone HSP27 (HSPB1) in cancer progression, and the demand for drugs that modulate HSPB1-activity is increasing rapidly. We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in panc...

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Veröffentlicht in:Journal of cancer research and clinical oncology 2011-09, Vol.137 (9), p.1349-1361
Hauptverfasser: Heinrich, Jörg-Christian, Tuukkanen, Anne, Schroeder, Michael, Fahrig, Torsten, Fahrig, Rudolf
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container_issue 9
container_start_page 1349
container_title Journal of cancer research and clinical oncology
container_volume 137
creator Heinrich, Jörg-Christian
Tuukkanen, Anne
Schroeder, Michael
Fahrig, Torsten
Fahrig, Rudolf
description Background Several reports describe the importance of the chaperone HSP27 (HSPB1) in cancer progression, and the demand for drugs that modulate HSPB1-activity is increasing rapidly. We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer. Methods Chemistry : Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology : HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancer patients: Pilot study, Dose finding study, Phase II study (NCT00550004). Results Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancer patients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients. Conclusions The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.
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We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer. Methods Chemistry : Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology : HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancer patients: Pilot study, Dose finding study, Phase II study (NCT00550004). Results Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancer patients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients. Conclusions The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.</description><identifier>ISSN: 0171-5216</identifier><identifier>EISSN: 1432-1335</identifier><identifier>DOI: 10.1007/s00432-011-1005-1</identifier><identifier>PMID: 21833720</identifier><identifier>CODEN: JCROD7</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - metabolism ; Adenocarcinoma - mortality ; Animals ; Antineoplastic agents ; Antineoplastic Agents - administration &amp; dosage ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Bromodeoxyuridine - administration &amp; dosage ; Bromodeoxyuridine - analogs &amp; derivatives ; Bromodeoxyuridine - metabolism ; Bromodeoxyuridine - pharmacology ; Cancer Research ; Chemotherapy ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Evaluation, Preclinical ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Heat shock proteins ; Hematology ; HSP27 Heat-Shock Proteins - metabolism ; Humans ; Internal Medicine ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Medicine ; Medicine &amp; Public Health ; Middle Aged ; Models, Molecular ; Oncology ; Original Paper ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - mortality ; Pharmacology. 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We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer. Methods Chemistry : Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology : HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancer patients: Pilot study, Dose finding study, Phase II study (NCT00550004). Results Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancer patients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients. Conclusions The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.</description><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - mortality</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration &amp; dosage</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bromodeoxyuridine - administration &amp; dosage</subject><subject>Bromodeoxyuridine - analogs &amp; derivatives</subject><subject>Bromodeoxyuridine - metabolism</subject><subject>Bromodeoxyuridine - pharmacology</subject><subject>Cancer Research</subject><subject>Chemotherapy</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Drug Evaluation, Preclinical</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Heat shock proteins</subject><subject>Hematology</subject><subject>HSP27 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine &amp; Public Health</subject><subject>Middle Aged</subject><subject>Models, Molecular</subject><subject>Oncology</subject><subject>Original Paper</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - mortality</subject><subject>Pharmacology. 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Liver. Pancreas. Abdomen</topic><topic>Heat shock proteins</topic><topic>Hematology</topic><topic>HSP27 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine &amp; Public Health</topic><topic>Middle Aged</topic><topic>Models, Molecular</topic><topic>Oncology</topic><topic>Original Paper</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - mortality</topic><topic>Pharmacology. Drug treatments</topic><topic>Pilot Projects</topic><topic>Placebos</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sarcoma - metabolism</topic><topic>Sarcoma - mortality</topic><topic>Survival Analysis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heinrich, Jörg-Christian</creatorcontrib><creatorcontrib>Tuukkanen, Anne</creatorcontrib><creatorcontrib>Schroeder, Michael</creatorcontrib><creatorcontrib>Fahrig, Torsten</creatorcontrib><creatorcontrib>Fahrig, Rudolf</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>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><jtitle>Journal of cancer research and clinical oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Heinrich, Jörg-Christian</au><au>Tuukkanen, Anne</au><au>Schroeder, Michael</au><au>Fahrig, Torsten</au><au>Fahrig, Rudolf</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients</atitle><jtitle>Journal of cancer research and clinical oncology</jtitle><stitle>J Cancer Res Clin Oncol</stitle><addtitle>J Cancer Res Clin Oncol</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>137</volume><issue>9</issue><spage>1349</spage><epage>1361</epage><pages>1349-1361</pages><issn>0171-5216</issn><eissn>1432-1335</eissn><coden>JCROD7</coden><abstract>Background Several reports describe the importance of the chaperone HSP27 (HSPB1) in cancer progression, and the demand for drugs that modulate HSPB1-activity is increasing rapidly. We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer. Methods Chemistry : Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology : HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancer patients: Pilot study, Dose finding study, Phase II study (NCT00550004). Results Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancer patients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients. Conclusions The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>21833720</pmid><doi>10.1007/s00432-011-1005-1</doi><tpages>13</tpages></addata></record>
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subjects Adenocarcinoma - drug therapy
Adenocarcinoma - metabolism
Adenocarcinoma - mortality
Animals
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Biological and medical sciences
Bromodeoxyuridine - administration & dosage
Bromodeoxyuridine - analogs & derivatives
Bromodeoxyuridine - metabolism
Bromodeoxyuridine - pharmacology
Cancer Research
Chemotherapy
Disease Models, Animal
Dose-Response Relationship, Drug
Double-Blind Method
Drug Evaluation, Preclinical
Female
Gastroenterology. Liver. Pancreas. Abdomen
Heat shock proteins
Hematology
HSP27 Heat-Shock Proteins - metabolism
Humans
Internal Medicine
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Medicine
Medicine & Public Health
Middle Aged
Models, Molecular
Oncology
Original Paper
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - mortality
Pharmacology. Drug treatments
Pilot Projects
Placebos
Rats
Rats, Sprague-Dawley
Sarcoma - metabolism
Sarcoma - mortality
Survival Analysis
Tumors
title RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients
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