Document Detail

Anti-cancer actions of a recombinant antibody (R6313/G2) against the angiotensin II AT1 receptor.
MedLine Citation:
PMID:  18310294     Owner:  NLM     Status:  MEDLINE    
Although several tumour types express both AT1 and AT2 angiotensin II receptors, and angiotensin II stimulates cell proliferation, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are not effective anti-cancer agents. Development of a biologically active monoclonal antibody (6313/G2) against the AT1 receptor prompted the testing of a recombinant short-chain variable fragment form (R6313/G2) against breast cancer cells in vitro and in vivo. Cell lines MCF-7, MDA-MB-231 and T47D all expressed both receptor subtypes. In vitro, R6313/G2 suppressed cell proliferation in the presence of 100 nM angiotensin II, with IC50s of 30 nM, 153 nM and 2.8 microM for the three cell types respectively; in contrast, the AT1 receptor blocker losartan was effective only in T47D cells, at 25 microM. Studies on MCF-7 and T47D cells showed R6313/G2 also opposed the angiotensin II-induced inhibition of caspase-3/7 activity. In vivo, hollow fibres containing the cell lines were implanted in nu/nu balb-c mice at two sites, s.c. and i.p. Treatments of R6313/G2 at 2.5 nmol/kg and 25 nmol/kg twice per day for 7 days dose dependently reduced cell numbers for all three cell lines, but here MCF-7 cells responded most sensitively and MDA-MB-231 cells least. Although T47D cells were refractory at the s.c. site, growth was inhibited at the i.p. location, and otherwise results were similar at the two sites. In xenografts, MCF-7 cell tumours were dose dependently reduced by R6313/G2, and 13 and 27 nmol/kg R6313/G2 twice/day gave means of 74 and 76% tumour regression after 7 days. The data suggest that the anti-cancer action of R6313/G2 is considerably more effective than AT1 antagonists.
M A Redondo-Müller; M Stevanovic-Walker; S Barker; J R Puddefoot; G P Vinson
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Endocrine-related cancer     Volume:  15     ISSN:  1351-0088     ISO Abbreviation:  Endocr. Relat. Cancer     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-03     Completed Date:  2008-05-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9436481     Medline TA:  Endocr Relat Cancer     Country:  England    
Other Details:
Languages:  eng     Pagination:  277-88     Citation Subset:  IM    
School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK.
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MeSH Terms
Angiotensin II / pharmacology
Angiotensin II Type 1 Receptor Blockers / therapeutic use
Antibodies, Monoclonal / therapeutic use*
Blood Pressure Determination
Blotting, Western
Breast Neoplasms / immunology*,  metabolism,  therapy*
Caspases / metabolism
Cell Survival
Immunoglobulin Fragments / genetics,  immunology
Losartan / therapeutic use
Mice, Inbred BALB C
Peptide Fragments / immunology,  metabolism
Rats, Wistar
Receptor, Angiotensin, Type 1 / immunology*,  metabolism
Receptor, Angiotensin, Type 2 / antagonists & inhibitors,  immunology*,  metabolism
Recombinant Proteins / genetics,  immunology,  therapeutic use*
Tumor Cells, Cultured
Vasoconstrictor Agents / pharmacology
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Antibodies, Monoclonal; 0/Immunoglobulin Fragments; 0/Peptide Fragments; 0/Receptor, Angiotensin, Type 1; 0/Receptor, Angiotensin, Type 2; 0/Recombinant Proteins; 0/Vasoconstrictor Agents; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; EC 3.4.22.-/Caspases

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