Sunitinib Acts Primarily on Tumor Endothelium rather than Tumor Cells to Inhibit the Growth of Renal Cell Carcinoma

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作者：

D Huang，Y Ding，Y Li，Luo, W.-M.，Zhang, Z.-F.，J Snider，VandenBeldt, K.，Qian, C.-N.，BT Teh

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摘要：

Sunitinib is a broad-spectrum small-molecule inhibitor of receptor tyrosine kinases (RTK) that serves as the present standard of care for first-line therapy of advanced clear cell renal cell carcinoma (ccRCC). A full understanding of the targets and mechanism of action of sunitinib in ccRCC treatment remains incomplete. In this study, we evaluated several tumor cell and endothelial targets of sunitinib and investigated which RTK(s) may specifically contribute to its therapeutic effects. Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets, only platelet-derived growth factor receptor-beta and vascular endothelial growth factor receptor-2 (VEGFR-2) were overexpressed in ccRCCs relative to normal tissues. Sunitinib was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations (approximately 0.1 micromol/L) that inhibit RTK targets. In contrast, sunitinib inhibited endothelial cell proliferation and motility at the same concentrations by suppressing VEGFR-2 signaling. Moreover, whereas sunitinib inhibited the growth of ccRCC xenograft tumors and decreased tumor microvessel density as soon as 12 hours after treatment, sunitinib showed no significant effects on tumor cell proliferation or apoptosis up to 72 hours after treatment. Our findings indicate that sunitinib inhibits ccRCC growth primarily through an antiangiogenic mechanism and not through direct targeting of ccRCC tumor cells.

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关键词：

cellulose bioenergy agriculture lignin cell wall cellulose synthase

DOI：

10.1158/0008-5472.CAN-09-3722

被引量：

361

年份：

2010