This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sini, P. Articles by Hynes, N. E. Search for Related Content PubMed PubMed Citation Articles by Sini, P. Articles by Hynes, N. E.

Inhibition of Multiple Vascular Endothelial Growth Factor Receptors (VEGFR) Blocks Lymph Node Metastases but Inhibition of VEGFR-2 Is Sufficient to Sensitize Tumor Cells to Platinum-Based Chemotherapeutics

¹ Friedrich Miescher Institute for Biomedical Research; ² Novartis Institute for Biomedical Research, Basel, Switzerland; ³ Joint Research Division Vascular Biology of the Medical Faculty Mannheim, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany; ⁴ Therapeutic Research Group Oncology, Bayer Schering Pharma AG, Berlin, Germany; and ⁵ Department of Medical Oncology, Erasmus Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands

Requests for reprints: Patrizia Sini, AstraZeneca Pharmaceutical, Cancer and Infection, Alderley Park, Macclesfield, Cheshire, United Kingdom. Phone: 44-1625233696; E-mail: patrizia.sini{at}astrazeneca.com.

Key Words: VEGFR • lymphangiogenesis • metastases • chemotherapy

Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared the efficacy of a VEGFR tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), which targets the three VEGFRs, with blocking antibodies directed against VEGFR-2 (DC101) or VEGF-A (Pab85618) in a metastatic melanoma model. Although all inhibitors exerted comparable effects on primary tumor growth, only PTK/ZK significantly reduced lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the metastases. However, the functionality of lymphatics surrounding the primary tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a breast carcinoma model. B16/BL6 tumor cells express VEGF ligands and their receptors. Blockade of a VEGFR-1 autocrine loop with PTK/ZK inhibited tumor cell migration. Furthermore, the tumor cells also showed enhanced sensitivity to platinum-based chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of tumor pathophysiology, including lymphatic vessel functionality, tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds. [Cancer Res 2008;68(5):1581–92]

This article has been cited by other articles:

				R. Marone, D. Erhart, A. C. Mertz, T. Bohnacker, C. Schnell, V. Cmiljanovic, F. Stauffer, C. Garcia-Echeverria, B. Giese, S.-M. Maira, et al. Targeting Melanoma with Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitors Mol. Cancer Res., April 1, 2009; 7(4): 601 - 613. [Abstract] [Full Text] [PDF]

				H. A. Lane, J. M. Wood, P. M.J. McSheehy, P. R. Allegrini, A. Boulay, J. Brueggen, A. Littlewood-Evans, S.-M. Maira, G. Martiny-Baron, C. R. Schnell, et al. mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor Clin. Cancer Res., March 1, 2009; 15(5): 1612 - 1622. [Abstract] [Full Text] [PDF]

				T. Schomber, A. Zumsteg, K. Strittmatter, I. Crnic, H. Antoniadis, A. Littlewood-Evans, J. Wood, and G. Christofori Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis Mol. Cancer Ther., January 1, 2009; 8(1): 55 - 63. [Abstract] [Full Text] [PDF]