Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients.

Willett, C.G., Boucher, Y., Duda, D.G., di Tomaso, E., Munn, L.L., Tong, R.T., Kozin, S.V., Petit, L., Jain, R.K., Chung, D.C., Sahani, D.V., Kalva, S.P., Cohen, K.S., Scadden, D.T., Fischman, A.J., Clark, J.W., Ryan, D.P., Zhu, A.X., Blaszkowsky, L.S., Shellito, P.C., Mino-Kenudson, M., Lauwers, G.Y.
Journal   J Clin Oncology.
Species  
Analytes Measured   PlGF , Flt-1 VEGFR1
Matrix Tested   Plasma
Year   2005
Volume   23
Page Numbers   8136-8139
Application   Cytokines and Chemokines
Abstract
PURPOSE: To determine whether SB-267268, a nonpeptidic antagonist of the alpha(v)beta3 and alpha(v)beta5 integrins, attenuates angiogenesis in a murine model of retinopathy of prematurity (ROP) and alters the expression of vascular endothelial growth factor (VEGF) and its second receptor (VEGF-R2).

METHODS: In receptor binding, SB-267268 exhibited nanomolar potency for human, monkey, and murine alpha(v)beta3 and alpha(v)beta5. SB-267268 inhibited the attachment of alpha(v)beta3-transfected HEK293 cells to microtiter plate wells precoated with RGD-containing matrix proteins, and vitronectin-mediated human and rat aortic smooth-muscle-cell migration. At postnatal day (P)12, C57BL/6 mice were exposed to 80% oxygen for 7 days followed by 7 days in room air (angiogenic period). Between P12 and P17, ROP mice were administered sterile saline (vehicle intraperitoneal [i.p.]) or SB-267268 (60 mg/kg bi-daily, i.p.). Shams were exposed to room air from P0 and administered either vehicle or SB-267268 during P12 to 17. In at least 3 randomly chosen paraffin sections from each eye, the number of blood vessel profiles in the inner retina were counted. In situ hybridization for VEGF and VEGFR-2 was performed on at least 8 randomly chosen paraffin sections from each eye.

RESULTS: SB-267268 reduced pathologic angiogenesis in ROP mice by approximately 50% and had no effect on developmental retinal angiogenesis in shams. Both VEGF and VEGFR-2 mRNA were upregulated in the inner retina of ROP mice and reduced with SB-267268.

CONCLUSIONS: Nonpeptidic inhibition of alpha(v)beta3 and alpha(v)beta5 integrins is effective in ROP and may be a suitable anti-angiogenic therapy for other ischemic retinal pathologies.

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