Please use this identifier to cite or link to this item:
Title: Altered efficacy of AT1R-targeted treatment after spontaneous cancer cell-AT1R upregulation.
Austin Authors: Ager, Eleanor I;Wen, Shu Wen;Chan, Joyna;Chong, Way W;Neo, Jaclyn H;Christophi, Christopher 
Affiliation: The Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia
Issue Date: 26-Jun-2011
Publication information: Bmc Cancer 2011; 11(): 274
Abstract: Targeting of the renin angiotensin system (RAS) reduces tumour growth in experimental models of cancer. We aimed to establish if combined targeting of the 'classical' and 'alternative' arms of the RAS could result in synergistic inhibition of colorectal cancer (CRC) liver metastases.Immediately following induction of CRC liver metastases through intrasplenic injection of murine CRC cells, treatment with irbesartan (AT1R blocker; 50 mg/kg/day s.c.), captopril (ACE inhibitor; 750 mg/kg/day i.p.), CGP42112A (AT2R agonist; 0.6 μg/kg/hr i.p.), and/or ANG-(1-7) (24 μg/kg/hr i.p.) began and continued for 21 days. Liver to body weight ratio and/or stereology were used as a measure of tumour burden. Immunohistochemistry was used to determine AT1R and VEGF expression as well as proliferation (Ki67), apoptosis (active caspase 3) and angiogenesis (CD34).Combined RAS therapies failed to improve upon single arm therapies. However, while irbesartan previously inhibited tumour growth in this model, in the current experiments irbesartan failed to affect tumour burden. Subsequent analysis showed a cancer-cell specific upregulation of the angiotensin II type I receptor (AT1R) in irbesartan-insensitive compared to irbesartan-sensitive tumours. The upregulation of AT1R was associated with an increase in proliferation and VEGF expression by cancer cells. While animals bearing irbesartan-sensitive tumours showed a marked decrease in the number of proliferating cells in the liver and VEGF-expressing infiltrating cells in the tumour following AT1R treatment, these were unchanged by treatment in animals bearing irbesartan-insensitive (high AT1R expressing) tumours.Although the results do not support increased efficacy of combined treatment, they provide intriguing evidence of the importance of RAS expression in determining patient response and tumour growth potential and suggest that components of the RAS could be used as biomarkers to aid in patient selection.
Gov't Doc #: 21703011
DOI: 10.1186/1471-2407-11-274
Type: Journal Article
Subjects: Adenocarcinoma.drug therapy.genetics.metabolism.secondary
Angiotensin I.pharmacology.therapeutic use
Angiotensin II Type 1 Receptor Blockers.pharmacology.therapeutic use
Angiotensin-Converting Enzyme Inhibitors.pharmacology.therapeutic use
Biphenyl Compounds.pharmacology.therapeutic use
Captopril.pharmacology.therapeutic use
Colorectal Neoplasms.drug therapy.genetics.metabolism
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Drug Synergism
Gene Expression Regulation, Neoplastic
Liver Neoplasms, Experimental.drug therapy.genetics.metabolism
Mice, Inbred CBA
Molecular Targeted Therapy
Neoplasm Proteins.antagonists & inhibitors.physiology
Neovascularization, Pathologic.drug therapy
Peptide Fragments.pharmacology.therapeutic use
Receptor, Angiotensin, Type 1.biosynthesis.drug effects.genetics
Receptor, Angiotensin, Type 2.agonists
Renin-Angiotensin System.physiology
Tetrazoles.pharmacology.therapeutic use
Tumor Burden
Tumor Markers, Biological
Vascular Endothelial Growth Factor A.biosynthesis.genetics
Appears in Collections:Journal articles

Files in This Item:
File Description SizeFormat 
21703011.pdf2.95 MBAdobe PDFThumbnail
Show full item record

Page view(s)

checked on Dec 5, 2022


checked on Dec 5, 2022

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.