Document Detail


Treatment of HER2-expressing breast cancer and ovarian cancer cells with alpha particle-emitting 227Th-trastuzumab.
MedLine Citation:
PMID:  21195878     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate (227)Th-p-isothiocyanato-benzyl-DOTA-trastuzumab ((227)Th-trastuzumab [where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]) internalized by breast and ovarian cancer cell lines in order to assess the potential of (227)Th-trastuzumab as a therapeutic agent against metastatic cancers that overexpress the HER2 oncogene.
METHODS AND MATERIALS: Clonogenic survival and cell growth rates of breast cancer cells treated with (227)Th-trastuzumab were compared with rates of cells treated with nonbinding (227)Th-rituximab, cold trastuzumab, and X-radiation. Cell growth experiments were also performed with ovarian cancer cells. Cell-associated radioactivity was measured at several time points, and the mean radiation dose to cells was calculated.
RESULTS: SKBR-3 cells got 50% of the mean absorbed radiation dose from internalized activity and 50% from cell surface-bound activity, while BT-474 and SKOV-3 cells got 75% radiation dose from internalized activity and 25% from cell surface-bound activity. Incubation of breast cancer cells with 2.5 kBq/ml (227)Th-trastuzumab for 1 h at 4°C, followed by washing, resulted in mean absorbed radiation doses of 2 to 2.5 Gy. A dose-dependent inhibition of cell growth and an increase in apoptosis were induced in all cell lines.
CONCLUSIONS: Clinically relevant activity concentrations of (227)Th-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of (227)Th-trastuzumab was higher than that of single-dose X-radiation (relative biological effectiveness = 1.2). These results warrant further studies of treatment of breast cancer and ovarian cancer with (227)Th-trastuzumab.
Authors:
Helen Heyerdahl; Cecilie Krogh; Jørgen Borrebæk; Åsmund Larsen; Jostein Dahle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of radiation oncology, biology, physics     Volume:  79     ISSN:  1879-355X     ISO Abbreviation:  Int. J. Radiat. Oncol. Biol. Phys.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-03     Completed Date:  2011-02-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603616     Medline TA:  Int J Radiat Oncol Biol Phys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  563-70     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Affiliation:
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal / pharmacokinetics,  therapeutic use*
Antibodies, Monoclonal, Murine-Derived / pharmacokinetics,  therapeutic use
Apoptosis / radiation effects*
Breast Neoplasms / genetics,  metabolism,  pathology,  radiotherapy*
Cell Line, Tumor
Cell Proliferation / radiation effects
Cell Survival / radiation effects*
Female
Genes, erbB-2*
Humans
Immunoconjugates / pharmacokinetics,  therapeutic use*
Neoplasm Proteins / metabolism
Organometallic Compounds / pharmacokinetics,  therapeutic use*
Ovarian Neoplasms / genetics,  metabolism,  pathology,  radiotherapy*
Radiotherapy Dosage
Receptor, erbB-2 / metabolism
Relative Biological Effectiveness
Tumor Stem Cell Assay / methods
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Murine-Derived; 0/Immunoconjugates; 0/Neoplasm Proteins; 0/Organometallic Compounds; 0/thorium-227-DOTA-rituximab; 0/thorium-227-p-isothiocyanato-benzyl-DOTA-trastuzumab; EC 2.7.10.1/Receptor, erbB-2

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