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

被引：388

作者：

Reynolds, Andrew R. ^{[1
,3
]}

Hart, Ian R. ^{[2
]}

Watson, Alan R. ^{[1
]}

Welti, Jonathan C. ^{[3
]}

Silva, Rita G. ^{[1
]}

Robinson, Stephen D. ^{[1
]}

Da Violante, Georges ^{[4
]}

Gourlaouen, Morgane ^{[3
]}

Salih, Mishal ^{[1
]}

Jones, Matt C. ^{[5
]}

Jones, Dylan T. ^{[1
]}

Saunders, Garry ^{[6
]}

Kostourou, Vassiliki ^{[1
]}

Perron-Sierra, Francoise

Norman, Jim C. ^{[5
]}

Tucker, Gordon C. ^{[7
]}

Hodivala-Dilke, Kairbaan M. ^{[1
]}

机构：

[1] Queen Mary Univ London, Barts & London Sch Med & Dent, Inst Canc,John Vane Sci Ctr, Adhes & Angiogenesis Lab, London, England

[2] Queen Mary Univ London, Barts & London Sch Med & Dent, Inst Canc,John Vane Sci Ctr, Tumor Biol Ctr, London, England

[3] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Tumour Angiogenesis Grp, London SW3 6JB, England

[4] Technol Servier, Orleans, France

[5] Beatson Inst Canc Res, Integrin Cell Biol Lab, Glasgow G61 1BD, Lanark, Scotland

[6] Canc Res UK London Res Inst, Clare Hall Labs, S Mimms, Herts, England

[7] Inst Rech Servier, Canc Res & Drug Discovery Div, Croissy Sur Seine, France

来源：

NATURE MEDICINE | 2009年 / 15卷 / 04期

关键词：

ADVANCED SOLID TUMORS; ENDOTHELIAL-CELLS; IN-VIVO; PATHOLOGICAL ANGIOGENESIS; ALPHA-V-BETA-3; INTEGRIN; CILENGITIDE EMD-121974; MALIGNANT GLIOMA; BREAST-CANCER; PHASE-I; ALPHA;

D O I：

10.1038/nm.1941

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：392 / 400

页数：9

共 54 条

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