Document Detail


Cellular and molecular properties of (90)Y-labeled cetuximab in combination with radiotherapy on human tumor cells in vitro.
MedLine Citation:
PMID:  22875052     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Anti-EGFR antibody cetuximab (C225) is used in combination with radiotherapy of head and neck squamous cell carcinoma (HNSCC) patients. We investigated whether conjugation of cetuximab with trans-cyclohexyl-diethylene-triamine-pentaacetic acid (CHX-A″-DTPA) and radiolabeling with (90)Yttrium affect the molecular and cellular function of cetuximab and improve its combined effect with external-beam irradiation (EBI).
METHODS: The following cell lines were used: HNSCC UT5, SAS, FaDu, as well as A43, Chinese hamster ovary cells (CHO), and human skin fibroblast HSF7. Binding affinity and kinetics, specificity, retention, and the combination of (90)Y-cetuximab with EBI were evaluated.
RESULTS: Control cetuximab and CHX-A″-DTPA-cetuximab blocked the proliferation activity of UT5 cells. In combination with EBI, CHX-A″-DTPA-cetuximab increased the radiosensitivity of UT5 to a similar degree as control cetuximab did. In contrast, in SAS and HSF7 cells neither proliferation nor radiosensitivity was affected by either of the antibodies. Binding [(90)Y]Y-CHX-A″-DTPA-cetuximab ((90)Y-cetuximab) to EGFR in HNSCC cells occurred time dependently with a maximum binding at 24 h. Retention of (90)Y-cetuximab was similar in both HNSCC cell lines; 24 h after treatment, approximately 90% of bound activity remained in the cell layer. Competition assays, using cell membranes in the absence of an internalized fraction of cetuximab, showed that the cetuximab affinity is not lost as a result of conjugation with CHX-A″-DTPA. Cetuximab and CHX-A″-DTPA-cetuximab blocked EGF-induced Y1068 phosphorylation of EGFR. The lack of an effect of cetuximab on EGF-induced Akt and ERK1/2 phosphorylation and the inhibition of irradiation (IR)-induced Akt and ERK1/2 phosphorylation by cetuximab were not affected by DTPA conjugation. (90)Y-cetuximab in combination with EBI resulted in a pronounced inhibition of colony formation of HNSCC cells.
CONCLUSIONS: Conjugation of CHX-A″-DTPA to cetuximab does not alter the cellular and biological function of cetuximab. (90)Y-labeling of cetuximab in combination with EBI may improve radiotherapy outcome.
Authors:
M Saki; M Toulany; W Sihver; M Zenker; J-M Heldt; B Mosch; H-J Pietzsch; M Baumann; J Steinbach; H P Rodemann
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-10
Journal Detail:
Title:  Strahlentherapie und Onkologie : Organ der Deutschen Röntgengesellschaft ... [et al]     Volume:  188     ISSN:  1439-099X     ISO Abbreviation:  Strahlenther Onkol     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-23     Completed Date:  2012-11-05     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8603469     Medline TA:  Strahlenther Onkol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  823-32     Citation Subset:  IM    
Affiliation:
Division of Radiobiology & Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal / administration & dosage*
Cell Line, Tumor
Cell Survival / drug effects,  radiation effects
Chemoradiotherapy, Adjuvant / methods*
Cricetinae
Humans
Neoplasms, Experimental / physiopathology*,  radiotherapy*
Radiation Dosage
Radiotherapy, Conformal / methods*
Yttrium Radioisotopes / administration & dosage*
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Yttrium Radioisotopes; PQX0D8J21J/cetuximab

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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