Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts

Abstract

BackgroundStudies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors.MethodsR-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker.ResultsProperdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors.ConclusionsProperdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3404-4) contains supplementary material, which is available to authorized users.

Understanding the Microenvironment of Melanoma Cells for the Development of Target Drug Delivery Systems

“…Both drugs were reported to inhibit angiogenesis; however, the drugs have had different effects on vascular morphology and function, and presented an extent of hypoxia in R-18 human melanoma xenografts. 52…”

Combination of 131I-anti-endoglin monoclonal antibody and 5-fluorouracil may be a promising combined-modality radioimmunotherapy strategy for the treatment of hepatocellular carcinoma

“…Antiangiogenic therapy is a highly attractive new method for the treatment of cancers [5]. It potentially overcomes some of the main problems that are related to other therapeutic agents for solid tumours, which result in poor delivery and tumour heterogeneity [6]. Therefore, it is necessary to develop antiangiogenic agents for cancer therapy.…”