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PMID: 19305413 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.

Nature medicine ·Vol. 15 ·No. 4 ·2009-04-00 ·Pages 392-400

Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, Da Violante G, Gourlaouen M, Salih M, Jones MC, Jones DT, Saunders G, Kostourou V, Perron-Sierra F, Norman JC, Tucker GC, Hodivala-Dilke KM

Abstract

Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.

MeSH Terms
Angiogenesis Inhibitors/therapeutic use Animals Disease Models, Animal Humans Integrin alphaVbeta3/therapeutic use Lung Neoplasms/blood supply,drug therapy,pathology Melanoma, Experimental/blood supply,drug therapy,pathology Mice Neoplasms/blood supply,drug therapy Neovascularization, Pathologic/prevention & control Oligopeptides/pharmacology,therapeutic use Receptors, Vitronectin/therapeutic use Vascular Endothelial Growth Factor A/pharmacology
Chemicals
Angiogenesis Inhibitors Integrin alphaVbeta3 Oligopeptides Receptors, Vitronectin Vascular Endothelial Growth Factor A integrin alphaVbeta5 arginyl-glycyl-aspartic acid
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Reynolds Andrew R
Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. [email protected]
Hart Ian R
Watson Alan R
Welti Jonathan C
Silva Rita G
Robinson Stephen D
Da Violante Georges
Gourlaouen Morgane
Salih Mishal
Jones Matt C
Jones Dylan T
Saunders Garry
Kostourou Vassiliki
Perron-Sierra Françoise
Norman Jim C
Tucker Gordon C
Hodivala-Dilke Kairbaan M
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.1941
Email
[email protected]
Published
2009-04-00
Epub
2009-00-22
Pages
392-400
Language
English
Region
United States
NLM ID
9502015
Subset
IM
Grants
Breast Cancer Now · BREAST CANCER NOW RESEARCH CENTRE · United Kingdom
Cancer Research UK · United Kingdom
Corrections
CommentIn
PMID: 19584855
External Links
PubMed source DOI: 10.1038/nm.1941 View journal details
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