Document Detail


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:
PMID:  22736376     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Aisha Fasih; Humphrey Fonge; Zhongli Cai; Jeffrey V Leyton; Ilia Tikhomirov; Susan J Done; Raymond M Reilly
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-27
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  135     ISSN:  1573-7217     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-08     Completed Date:  2013-01-24     Revised Date:  2013-05-08    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  189-200     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.
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MeSH Terms
Descriptor/Qualifier:
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:
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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