Abstract
It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention.
(c) 2002 Elsevier Science (USA).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin Receptor Antagonists*
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Animals
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Antihypertensive Agents / pharmacology
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Antineoplastic Agents / pharmacology
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Benzimidazoles / pharmacology*
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Biphenyl Compounds / pharmacology*
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Carcinoma, Lewis Lung / drug therapy*
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Carcinoma, Lewis Lung / metabolism
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Carcinoma, Lewis Lung / pathology
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Cell Division / drug effects
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Drug Screening Assays, Antitumor
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Fibrosarcoma / drug therapy*
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Fibrosarcoma / metabolism
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Fibrosarcoma / pathology
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Immunohistochemistry
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Lisinopril / pharmacology
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Male
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Inbred ICR
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Neoplasm Metastasis / prevention & control
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Neoplasm Transplantation
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Neovascularization, Pathologic / prevention & control
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Peptidyl-Dipeptidase A / biosynthesis
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Peptidyl-Dipeptidase A / genetics
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RNA, Messenger / biosynthesis
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin / biosynthesis
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Receptors, Angiotensin / genetics
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Sarcoma 180 / drug therapy
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Sarcoma 180 / metabolism
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Sarcoma 180 / pathology
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Sarcoma, Experimental / drug therapy*
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Sarcoma, Experimental / metabolism
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Sarcoma, Experimental / pathology
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Signal Transduction / drug effects*
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Tetrazoles*
Substances
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Angiotensin Receptor Antagonists
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Antihypertensive Agents
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Antineoplastic Agents
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Benzimidazoles
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Biphenyl Compounds
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RNA, Messenger
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin
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Tetrazoles
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Lisinopril
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Peptidyl-Dipeptidase A
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candesartan cilexetil