| Inhibition of vascular endothelial growth factor-a signaling induces hypertension: examining the effect of cediranib (recentin; AZD2171) treatment on blood pressure in rat and the use of concomitant antihypertensive therapy. | |
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MedLine Citation:
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PMID: 18483380 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a key therapeutic approach in oncology given the role of VEGF in angiogenesis and vascular permeability in solid tumors. Clinical trials examining VEGF signaling inhibitors commonly report hypertension. We examined the effect of cediranib, a highly potent VEGF signaling inhibitor, on the blood pressure of rats and the ability of standard antihypertensive agents to modulate the consequences of VEGF signaling inhibition. EXPERIMENTAL DESIGN: The ability of cediranib to induce hypertensive changes and the effect of giving antihypertensive therapy were investigated in conscious, unrestrained telemetered rats. Two antihypertensive agents were studied: captopril, an angiotensin-converting enzyme inhibitor, and nifedipine, a dihydropyridine calcium channel blocker. The antitumor activity of cediranib, alone and in combination with nifedipine, was also evaluated in a LoVo human colorectal tumor xenograft model in nude rats. All treatments were given orally. RESULTS: Administration of 0.1 to 1.5 mg/kg/d of cediranib for 4 consecutive days induced a relatively mild hypertensive effect, elevating diastolic blood pressure by 10 to 14 mmHg. Dosing 3 mg/kg/d cediranib for 4 days induced a marked hypertension of 35 to 50 mmHg. Captopril (30 mg/kg, qd) was effective at lowering a 10 mmHg increase in blood pressure but not a 35 to 50 mmHg increase. However, the latter was rapidly reversed by administration of nifedipine (10 mg/kg, bd). Coadministration of nifedipine did not negatively affect the antitumor activity of cediranib (1.5 mg/kg/d). CONCLUSIONS: Hypertension is a direct consequence of inhibiting VEGF signaling but can be controlled with appropriately selected, standard antihypertensive medication. |
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Authors:
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Jon O Curwen; Helen L Musgrove; Jane Kendrew; Graham H P Richmond; Donald J Ogilvie; Stephen R Wedge |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 14 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-05-16 Completed Date: 2008-08-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3124-31 Citation Subset: IM |
Affiliation:
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Department of Cancer Bioscience, AstraZeneca, Macclesfield, Cheshire, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiogenesis Inhibitors
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pharmacology* Animals Antihypertensive Agents / pharmacology Antineoplastic Agents / pharmacology Blood Pressure / drug effects* Captopril / pharmacology Cell Line, Tumor Colorectal Neoplasms / drug therapy Humans Hypertension / drug therapy* Mice Nifedipine / pharmacology Quinazolines / pharmacology* Rats Signal Transduction / drug effects* Vascular Endothelial Growth Factor A / antagonists & inhibitors, drug effects, metabolism* Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline; 0/Angiogenesis Inhibitors; 0/Antihypertensive Agents; 0/Antineoplastic Agents; 0/Quinazolines; 0/Vascular Endothelial Growth Factor A; 21829-25-4/Nifedipine; 62571-86-2/Captopril |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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