Amifostine Inhibits Angiogenesis in Vivo

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Abstract
Amifostine (WR-2721) is an inorganic thiophosphate-cytoprotective agent developed to selectively protect normal tissues against the toxicity of chemotherapy and radiation. We have previously shown that amifostine protects both chicken embryo chorioallantoic membrane (CAM) vessels and cells from the effects of X-rays. In the present work, we studied the effect of amifostine on angiogenesis in vivo, using the CAM model. Amifostine decreased the number of CAM vessels in a dose-dependent manner, without being toxic for the tissue. It also decreased the mRNA levels of both vascular endothelial growth factor (VEGF) isoforms VEGF165 and VEGF190, 6 and up to 48 h after its application onto the CAM. Similarly, it decreased the mRNA levels of inducible nitric-oxide synthase, 24 and 48 h after drug application. Furthermore, amifostine decreased the deposited amounts of laminin and collagen I 24 h after its application, without affecting the expression of the corresponding genes. The protein amounts and activity of matrix metalloproteinase-2 were not affected, whereas the expression of the corresponding gene was decreased up to 48 h after drug application. Finally, the activity of plasmin was increased 6 h after amifostine application and remained increased at later time points. These findings suggest that amifostine alters the expression of several molecules implicated in the angiogenesis process and affects the composition of the extracellular matrix in a way that leads to inhibition of angiogenesis. Such an antiangiogenic action of amifostine, together with its radioprotective effects, further supports its use in combination with radiotherapy for increased therapeutic efficacy.