| 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. | |
MedLine Citation:
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PMID: 22736376 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
Authors:
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Aisha Fasih; Humphrey Fonge; Zhongli Cai; Jeffrey V Leyton; Ilia Tikhomirov; Susan J Done; Raymond M Reilly |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-06-27 |
Journal Detail:
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Title: Breast cancer research and treatment Volume: 135 ISSN: 1573-7217 ISO Abbreviation: Breast Cancer Res. Treat. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-08-08 Completed Date: 2013-01-24 Revised Date: 2013-05-08 |
Medline Journal Info:
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Nlm Unique ID: 8111104 Medline TA: Breast Cancer Res Treat Country: Netherlands |
Other Details:
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Languages: eng Pagination: 189-200 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal, Humanized / pharmacology, therapeutic use* Breast Neoplasms / metabolism, 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*, therapeutic use Radioimmunotherapy* Receptor, Epidermal Growth Factor / immunology, metabolism* Tissue Distribution |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal, Humanized; 0/DTPA-IgG complex; 0/Immunoconjugates; 0/Immunoglobulin G; 0/Indium Radioisotopes; 0/Nuclear Localization Signals; 0/nimotuzumab; 67-43-6/Pentetic Acid; EC 2.7.10.1/Receptor, Epidermal Growth Factor; P188ANX8CK/trastuzumab |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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