Differential Response of Primary Tumor Versus Lymphatic Metastasis to VEGFR-2 and VEGFR-3 Kinase Inhibitors Cediranib and Vandetanib

Overview

Journal Mol Cancer Ther

Date 2008 Aug 9

PMID 18687659

Citations 54

Authors

Timothy P Padera

Angera H Kuo

Tohru Hoshida

Shan Liao

Jennifer Lobo

Kevin R Kozak

Dai Fukumura

Rakesh K Jain

Affiliations

Soon will be listed here.

Abstract

Blood vessels are required for a tumor to grow and functional lymphatic vessels are required for it to disseminate to lymph nodes. In an attempt to eradicate both the primary tumor and its lymphatic metastasis, we targeted both blood and lymphatic vessels using two different tyrosine kinase inhibitors (TKIs): cediranib and vandetanib, which block vascular endothelial growth factor receptor (VEGFR)-2 and -3 in enzymatic assays. We found that although both cediranib and vandetanib slowed the growth rate of primary tumors and reduced blood vessel density, neither agent was able to prevent lymphatic metastasis when given after tumor cells had seeded the lymph node. However, when given during tumor growth, cediranib reduced the diameters of the draining lymphatic vessels, the number of tumor cells arriving in the draining lymph node, and the incidence of lymphatic metastasis. On the other hand, vandetanib had minimal effect on any of these variables, suggesting that vandetanib did not effectively block VEGFR-3 on lymphatic endothelial cells in our animal model. Collectively, these data indicate that the response of lymphatic vessels to a TKI can determine the incidence of lymphatic metastasis, independent of the effect of the TKI on blood vessels.

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