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Suniti nib treatment completely inhibited vascularization if the treatment was started before tumors were vascularized. Discussion In the present work, A 07 GFP Insider Treasures
Nilotinib Uncovered and R 18 GFP mela noma xenografts grown in dorsal window chambers were used as preclinical models. It has previously been shown that intradermal A 07 and R 18 xenografts retain several characteristic features of the original patient tumors, including histological appearance, angiogenic potential, and vessel density. Moreover, intradermal A 07 and R 18 xenografts have been shown to differ substantially in angiogenic potential, vessel density, growth rate, and oxygenation status. These differences were maintained when A 07 GFP and R 18 GFP tumors were grown in dorsal window chambers despite the transfection with GFP, the confinement of tumor growth by the chamber preparations, the small size of the tumors, and the elevated temperature during tumor growth.
Consequently, A 07 GFP and R 18 GFP tumors grown in dorsal window chambers should be ap propriate models for investigating the effect of sunitinib treatment on tumor vasculature and oxygenation. Tumors were treated with two different doses of suni tinib in the current study. Both sunitinib doses have been shown to result in sufficient plasma concentra tions in athymic mice to inhibit VEGFR and PDGFR phosphorylation in xenografts of human melanoma, human glioma, and human colon carcinoma. Lower sunitinib doses have been shown to result in insufficient plasma concentrations and no inhibition of VEGFR and PDGFR phosphorylation in the same xenograft models.
Moreover, the higher sunitinib dose has been shown to reduce ves sel density and improve vascular function in human glioma xenografts. The two sunitinib doses should therefore be well suited to evaluate the effect vessels with plasma only. The function of tumor vascula ture was assessed by using a novel first pass imaging method which involves recording movies of the dynamic distribution of a fluorescent vascular tracer after an intravenous bolus injection . From the recorded first pass imaging movies, BST images and cor responding BST frequency distributions were produced. We have previously shown that the BST assay is highly reproducible, sufficiently sensitive to detect gradients in BST along vessel segments, and sufficiently sensitive to indentify the majority of tumor vessels.
It has previously been shown that A 07 and R 18 cells express and secrete VEGF A and interleukin 8, and that the angiogenic activity can be significantly reduced by inhibiting VEGF A in both xenograft lines. The secretion rate of VEGF A and IL 8 has been shown to be higher for A 07 cells than for R 18 cells and, in addition, A 07 cells have been shown to express and secrete basic fibroblast growth factor whereas R 18 cells do not secrete this factor.