¹¹¹In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer.
Identifieur interne : 000923 ( Main/Exploration ); précédent : 000922; suivant : 000924¹¹¹In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer.
Auteurs : RBID : pubmed:22736376English descriptors
- KwdEn :
- Animals, Antibodies, Monoclonal, Humanized (pharmacology), Antibodies, Monoclonal, Humanized (therapeutic use), Breast Neoplasms (metabolism), Breast Neoplasms (radiotherapy), Cell Line, Tumor, DNA Damage (radiation effects), Drug Resistance, Neoplasm, Female, Humans, Immunoconjugates (therapeutic use), Immunoglobulin G (therapeutic use), Indium Radioisotopes (therapeutic use), Mice, Nuclear Localization Signals, Pentetic Acid (analogs & derivatives), Pentetic Acid (therapeutic use), Radioimmunotherapy, Receptor, Epidermal Growth Factor (immunology), Receptor, Epidermal Growth Factor (metabolism), Tissue Distribution.
- MESH :
- chemical , analogs & derivatives : Pentetic Acid.
- chemical , immunology : Receptor, Epidermal Growth Factor.
- chemical , metabolism : Receptor, Epidermal Growth Factor.
- chemical , pharmacology : Antibodies, Monoclonal, Humanized.
- chemical , therapeutic use : Antibodies, Monoclonal, Humanized, Immunoconjugates, Immunoglobulin G, Indium Radioisotopes, Pentetic Acid.
- metabolism : Breast Neoplasms.
- radiation effects : DNA Damage.
- radiotherapy : Breast Neoplasms.
- Animals, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Mice, Nuclear Localization Signals, Radioimmunotherapy, Tissue Distribution.
Abstract
Increased expression of epidermal growth factor receptors (EGFR) in breast cancer (BC) is often associated with trastuzumab (Herceptin)-resistant forms of the disease and represents an attractive target for novel therapies. Nimotuzumab is a humanized IgG(1) monoclonal antibody that is in clinical trials for treatment of EGFR-overexpressing malignancies. We show here that nimotuzumab derivatized with benzylisothiocyanate diethylenetriaminepentaacetic acid for labelling with the subcellular range Auger electron-emitter, (111)In and modified with nuclear translocation sequence (NLS) peptides ((111)In-NLS-Bn-DTPA-nimotuzumab) was bound, internalized and transported to the nucleus of EGFR-positive BC cells. Emission of Auger electrons in close proximity to the nucleus caused multiple DNA double-strand breaks which diminished the clonogenic survival (CS) of MDA-MB-468 cells that have high EGFR density (2.4 × 10(6) receptors/cell) to less than 3 %. (111)In-Bn-DTPA-nimotuzumab without NLS peptide modification was sevenfold less effective for killing MDA-MB-468 cells. (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification were equivalently cytotoxic to MDA-MB-231 and TrR1 BC cells that have moderate EGFR density (5.4 × 10(5) or 4.2 × 10(5) receptors/cell, respectively) reducing their CS by twofold. MDA-MB-231 cells have intrinsic trastuzumab resistance due to low HER2 density, whereas TrR1 cells have acquired resistance despite HER2 overexpression. Biodistribution and microSPECT/CT imaging revealed that (111)In-NLS-Bn-DTPA-nimotuzumab exhibited more rapid elimination from the blood and lower tumour uptake than (111)In-Bn-DTPA-nimotuzumab. Tumour uptake of the radioimmunoconjugates in mice with MDA-MB-468 xenografts was high (8-16 % injected dose/g) and was blocked by administration of an excess of unlabelled nimotuzumab, demonstrating EGFR specificity. We conclude that (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification are promising Auger electron-emitting radioimmunotherapeutic agents for EGFR-positive BC, but (111)In-Bn-DTPA-nimotuzumab may be preferred due to its higher tumour uptake in vivo.
DOI: 10.1007/s10549-012-2137-y
PubMed: 22736376
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">¹¹¹In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer.</title><author><name sortKey="Fasih, Aisha" uniqKey="Fasih A">Aisha Fasih</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON</wicri:regionArea></affiliation></author><author><name sortKey="Fonge, Humphrey" uniqKey="Fonge H">Humphrey Fonge</name></author><author><name sortKey="Cai, Zhongli" uniqKey="Cai Z">Zhongli Cai</name></author><author><name sortKey="Leyton, Jeffrey V" uniqKey="Leyton J">Jeffrey V Leyton</name></author><author><name sortKey="Tikhomirov, Ilia" uniqKey="Tikhomirov I">Ilia Tikhomirov</name></author><author><name sortKey="Done, Susan J" uniqKey="Done S">Susan J Done</name></author><author><name sortKey="Reilly, Raymond M" uniqKey="Reilly R">Raymond M Reilly</name></author></titleStmt><publicationStmt><date when="2012">2012</date><idno type="doi">10.1007/s10549-012-2137-y</idno><idno type="RBID">pubmed:22736376</idno><idno type="pmid">22736376</idno><idno type="wicri:Area/Main/Corpus">000C28</idno><idno type="wicri:Area/Main/Curation">000C28</idno><idno type="wicri:Area/Main/Exploration">000923</idno></publicationStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antibodies, Monoclonal, Humanized (pharmacology)</term><term>Antibodies, Monoclonal, Humanized (therapeutic use)</term><term>Breast Neoplasms (metabolism)</term><term>Breast Neoplasms (radiotherapy)</term><term>Cell Line, Tumor</term><term>DNA Damage (radiation effects)</term><term>Drug Resistance, Neoplasm</term><term>Female</term><term>Humans</term><term>Immunoconjugates (therapeutic use)</term><term>Immunoglobulin G (therapeutic use)</term><term>Indium Radioisotopes (therapeutic use)</term><term>Mice</term><term>Nuclear Localization Signals</term><term>Pentetic Acid (analogs & derivatives)</term><term>Pentetic Acid (therapeutic use)</term><term>Radioimmunotherapy</term><term>Receptor, Epidermal Growth Factor (immunology)</term><term>Receptor, Epidermal Growth Factor (metabolism)</term><term>Tissue Distribution</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Pentetic Acid</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Receptor, Epidermal Growth Factor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptor, Epidermal Growth Factor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antibodies, Monoclonal, Humanized</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antibodies, Monoclonal, Humanized</term><term>Immunoconjugates</term><term>Immunoglobulin G</term><term>Indium Radioisotopes</term><term>Pentetic Acid</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Breast Neoplasms</term></keywords><keywords scheme="MESH" qualifier="radiation effects" xml:lang="en"><term>DNA Damage</term></keywords><keywords scheme="MESH" qualifier="radiotherapy" xml:lang="en"><term>Breast Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Drug Resistance, Neoplasm</term><term>Female</term><term>Humans</term><term>Mice</term><term>Nuclear Localization Signals</term><term>Radioimmunotherapy</term><term>Tissue Distribution</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Increased expression of epidermal growth factor receptors (EGFR) in breast cancer (BC) is often associated with trastuzumab (Herceptin)-resistant forms of the disease and represents an attractive target for novel therapies. Nimotuzumab is a humanized IgG(1) monoclonal antibody that is in clinical trials for treatment of EGFR-overexpressing malignancies. We show here that nimotuzumab derivatized with benzylisothiocyanate diethylenetriaminepentaacetic acid for labelling with the subcellular range Auger electron-emitter, (111)In and modified with nuclear translocation sequence (NLS) peptides ((111)In-NLS-Bn-DTPA-nimotuzumab) was bound, internalized and transported to the nucleus of EGFR-positive BC cells. Emission of Auger electrons in close proximity to the nucleus caused multiple DNA double-strand breaks which diminished the clonogenic survival (CS) of MDA-MB-468 cells that have high EGFR density (2.4 × 10(6) receptors/cell) to less than 3 %. (111)In-Bn-DTPA-nimotuzumab without NLS peptide modification was sevenfold less effective for killing MDA-MB-468 cells. (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification were equivalently cytotoxic to MDA-MB-231 and TrR1 BC cells that have moderate EGFR density (5.4 × 10(5) or 4.2 × 10(5) receptors/cell, respectively) reducing their CS by twofold. MDA-MB-231 cells have intrinsic trastuzumab resistance due to low HER2 density, whereas TrR1 cells have acquired resistance despite HER2 overexpression. Biodistribution and microSPECT/CT imaging revealed that (111)In-NLS-Bn-DTPA-nimotuzumab exhibited more rapid elimination from the blood and lower tumour uptake than (111)In-Bn-DTPA-nimotuzumab. Tumour uptake of the radioimmunoconjugates in mice with MDA-MB-468 xenografts was high (8-16 % injected dose/g) and was blocked by administration of an excess of unlabelled nimotuzumab, demonstrating EGFR specificity. We conclude that (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification are promising Auger electron-emitting radioimmunotherapeutic agents for EGFR-positive BC, but (111)In-Bn-DTPA-nimotuzumab may be preferred due to its higher tumour uptake in vivo.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">22736376</PMID><DateCreated><Year>2012</Year><Month>08</Month><Day>08</Day></DateCreated><DateCompleted><Year>2013</Year><Month>01</Month><Day>24</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1573-7217</ISSN><JournalIssue CitedMedium="Internet"><Volume>135</Volume><Issue>1</Issue><PubDate><Year>2012</Year><Month>Aug</Month></PubDate></JournalIssue><Title>Breast cancer research and treatment</Title><ISOAbbreviation>Breast Cancer Res. Treat.</ISOAbbreviation></Journal><ArticleTitle>¹¹¹In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer.</ArticleTitle><Pagination><MedlinePgn>189-200</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1007/s10549-012-2137-y</ELocationID><Abstract><AbstractText>Increased expression of epidermal growth factor receptors (EGFR) in breast cancer (BC) is often associated with trastuzumab (Herceptin)-resistant forms of the disease and represents an attractive target for novel therapies. Nimotuzumab is a humanized IgG(1) monoclonal antibody that is in clinical trials for treatment of EGFR-overexpressing malignancies. We show here that nimotuzumab derivatized with benzylisothiocyanate diethylenetriaminepentaacetic acid for labelling with the subcellular range Auger electron-emitter, (111)In and modified with nuclear translocation sequence (NLS) peptides ((111)In-NLS-Bn-DTPA-nimotuzumab) was bound, internalized and transported to the nucleus of EGFR-positive BC cells. Emission of Auger electrons in close proximity to the nucleus caused multiple DNA double-strand breaks which diminished the clonogenic survival (CS) of MDA-MB-468 cells that have high EGFR density (2.4 × 10(6) receptors/cell) to less than 3 %. (111)In-Bn-DTPA-nimotuzumab without NLS peptide modification was sevenfold less effective for killing MDA-MB-468 cells. (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification were equivalently cytotoxic to MDA-MB-231 and TrR1 BC cells that have moderate EGFR density (5.4 × 10(5) or 4.2 × 10(5) receptors/cell, respectively) reducing their CS by twofold. MDA-MB-231 cells have intrinsic trastuzumab resistance due to low HER2 density, whereas TrR1 cells have acquired resistance despite HER2 overexpression. Biodistribution and microSPECT/CT imaging revealed that (111)In-NLS-Bn-DTPA-nimotuzumab exhibited more rapid elimination from the blood and lower tumour uptake than (111)In-Bn-DTPA-nimotuzumab. Tumour uptake of the radioimmunoconjugates in mice with MDA-MB-468 xenografts was high (8-16 % injected dose/g) and was blocked by administration of an excess of unlabelled nimotuzumab, demonstrating EGFR specificity. We conclude that (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification are promising Auger electron-emitting radioimmunotherapeutic agents for EGFR-positive BC, but (111)In-Bn-DTPA-nimotuzumab may be preferred due to its higher tumour uptake in vivo.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Fasih</LastName><ForeName>Aisha</ForeName><Initials>A</Initials><Affiliation>Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.</Affiliation></Author><Author ValidYN="Y"><LastName>Fonge</LastName><ForeName>Humphrey</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Cai</LastName><ForeName>Zhongli</ForeName><Initials>Z</Initials></Author><Author ValidYN="Y"><LastName>Leyton</LastName><ForeName>Jeffrey V</ForeName><Initials>JV</Initials></Author><Author ValidYN="Y"><LastName>Tikhomirov</LastName><ForeName>Ilia</ForeName><Initials>I</Initials></Author><Author ValidYN="Y"><LastName>Done</LastName><ForeName>Susan J</ForeName><Initials>SJ</Initials></Author><Author ValidYN="Y"><LastName>Reilly</LastName><ForeName>Raymond M</ForeName><Initials>RM</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType>Journal Article</PublicationType><PublicationType>Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>06</Month><Day>27</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Breast Cancer Res Treat</MedlineTA><NlmUniqueID>8111104</NlmUniqueID><ISSNLinking>0167-6806</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Antibodies, Monoclonal, Humanized</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>DTPA-IgG complex</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Immunoconjugates</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Immunoglobulin G</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Indium Radioisotopes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Nuclear Localization Signals</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>nimotuzumab</NameOfSubstance></Chemical><Chemical><RegistryNumber>7A314HQM0I</RegistryNumber><NameOfSubstance>Pentetic Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber><NameOfSubstance>Receptor, Epidermal Growth Factor</NameOfSubstance></Chemical><Chemical><RegistryNumber>P188ANX8CK</RegistryNumber><NameOfSubstance>trastuzumab</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Antibodies, Monoclonal, Humanized</DescriptorName><QualifierName MajorTopicYN="N">pharmacology</QualifierName><QualifierName MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Breast Neoplasms</DescriptorName><QualifierName MajorTopicYN="N">metabolism</QualifierName><QualifierName MajorTopicYN="Y">radiotherapy</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">DNA Damage</DescriptorName><QualifierName MajorTopicYN="N">radiation effects</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Drug Resistance, Neoplasm</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Immunoconjugates</DescriptorName><QualifierName MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Immunoglobulin G</DescriptorName><QualifierName MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Indium Radioisotopes</DescriptorName><QualifierName MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Nuclear Localization Signals</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Pentetic Acid</DescriptorName><QualifierName MajorTopicYN="Y">analogs & derivatives</QualifierName><QualifierName MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="Y">Radioimmunotherapy</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Receptor, Epidermal Growth Factor</DescriptorName><QualifierName MajorTopicYN="N">immunology</QualifierName><QualifierName MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Tissue Distribution</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2012</Year><Month>3</Month><Day>8</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2012</Year><Month>6</Month><Day>9</Day></PubMedPubDate><PubMedPubDate PubStatus="aheadofprint"><Year>2012</Year><Month>6</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>6</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>6</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>1</Month><Day>25</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="doi">10.1007/s10549-012-2137-y</ArticleId><ArticleId IdType="pubmed">22736376</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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