2009
DOI: 10.1038/nm.1941
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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 endothelia… Show more

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Cited by 422 publications
(367 citation statements)
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“…inhibitors were found to stimulate angiogenesis at low doses 181 . This has also been seen with oral α IIb β 3 antagonists, for which low doses were shown to induce platelet aggregation while higher doses were inhibitory 182 .…”
Section: Discussionmentioning
confidence: 99%
“…inhibitors were found to stimulate angiogenesis at low doses 181 . This has also been seen with oral α IIb β 3 antagonists, for which low doses were shown to induce platelet aggregation while higher doses were inhibitory 182 .…”
Section: Discussionmentioning
confidence: 99%
“…Along these lines, a recent report demonstrated that use of an osmotic minipump to deliver sustained nanomolar concentrations of RGD-mimetic integrin inhibitors promoted angiogenesis and tumor growth in B16F0 melanoma and LLC lung carcinoma cells grown subcutaneously in syngeneic C57BL6 mice [95]. However, exposure to micromolar concentrations of integrin inhibitors, which are typically achieved following pulse dosing in ongoing clinical trials, inhibits angiogenesis as measured by either microvessel sprouting of mouse aortic rings incubated with VEGF or by quantification of tubule formation in a fibroblast-HUVEC co-culture model.…”
Section: Pharmacodynamics and Preclinical Studiesmentioning
confidence: 99%
“…Cilengitide can be safely combined with chemotherapy and radiation therapy, and provides encouraging clinical anti-tumor activity so far. A recent preclinical study suggests that prolonged exposure to extremely low doses of RGD-mimetic integrin inhibitors may be associated with stimulation of tumor growth and angiogenesis [95]. Although this is not the dosing regimen used clinically with cilengitide and such findings have not been observed in the clinical application of antiintegrin agents to date [103] ongoing and future studies should evaluate such an adverse potential.…”
Section: Future Perspectivementioning
confidence: 99%
“…Interesting recent pre-clinical data have highlighted the potential importance of measuring the concentration of circulating tumour cells, which depend critically on tumour circulation for intravasation, as potential biomarkers of VEGF inhibitors (Ebos et al, 2009;Paez-Ribes et al, 2009;Reynolds et al, 2009).…”
Section: Future Directionsmentioning
confidence: 99%