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Effects of vatalanib on tumor growth can be potentiated by mTOR blockade in vivo

Jaeger-Lansky, Agnes and Cejka, Daniel and Ying, Liu and Presser, Matthias and Höflmayer, Doris and Fuereder, Thorsten and Köhrer, Stefan and Wacheck, Volker and Imark, Esther (2010) Effects of vatalanib on tumor growth can be potentiated by mTOR blockade in vivo. Cancer Biology & Therapy, 9 (11). pp. 919-927. ISSN 1538-4047

Abstract

Background: Vatalanib is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3. Vatalanib increases pro-angiogenic serum VEGF in response to VEGF receptor blockade which is considered to limit vatalinib´s anti-tumor activity. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) signaling and decreases VEGF-secretion of cells. It was hypothesized that inhibition of VEGF production by everolimus potentiates the anti-tumor activity of vatalanib.
Methods: In vitro, the effects of vatalanib and everolimus on gastric cancer cell proliferation, cell cycle, apoptosis and signal transduction were studied. Effects on angiogenesis were mimicked using tube formation assays of cultured human umbilical vein endothelial cells (HUVECs). In vivo, the anti-tumor effect of compounds was studied using a gastric cancer xenograft nude mouse model. VEGF production from the murine tumor host and human gastric cancer cells was analyzed by species specific ELISAs. Tumor vascularization and proliferation were studied by immunohistochemistry.
Results: In vitro, everolimus but not vatalanib decreased gastric cancer proliferation without affecting apoptosis. Vatalanib completely abolished endothelial cell tube formation, whereas inhibition of tube formation by everolimus was incomplete. In vivo, the combination of vatalanib with everolimus was superior to single agent treatment. Treatment with vatalanib + everolimus significantly decreased mVEGF levels but not hVEGF. Treatment with everolimus decreased hVEGF production significantly. There was a trend for lower vascular density and proliferation for combination treatment.
Conclusion: We conclude that anti-tumor activity of vatalanib can be augmented by everolimus in a preclinical model of gastric cancer, an effect potentially mediated by suppression of mVEGF production in the tumor microenvironment.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7106

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