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Open AccessArticle

Uptake of Ranibizumab but Not Bevacizumab into Uveal Melanoma Cells Correlates with a Sustained Decline in VEGF-A Levels and Metastatic Activities

1
Department of Ophthalmology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
2
Laboratory for Angiogenesis & Ocular Cell Transplantation, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
*
Author to whom correspondence should be addressed.
These authors share equal contribution.
Cancers 2019, 11(6), 868; https://doi.org/10.3390/cancers11060868
Received: 25 March 2019 / Revised: 17 June 2019 / Accepted: 17 June 2019 / Published: 21 June 2019
(This article belongs to the Special Issue Uveal Melanoma)
Despite the implication of vascular endothelial growth factor-A (VEGF-A) in the pathophysiology of uveal melanoma (UM), the anti-VEGF-A antibody bevacizumab yielded conflicting results on UM growth. Here, we evaluated whether bevacizumab and ranibizumab, a humanized Fab-fragment against VEGF-A, can enter UM cells and induce a sustained physiological response. The primary and metastatic UM cell lines Mel-270 and OMM-2.5 were exposed to bevacizumab or ranibizumab for one day and were maintained further in untreated medium for a total of three days. Both antibodies significantly reduced the levels of extracellular VEGF-A and the angiogenic potential of the conditioned medium after one day. These inhibitory effects of bevacizumab diminished by day three. Ranibizumab suppressed the metabolic activity, proliferation, and intracellular VEGF-A levels in a cell-type and concentration-dependent manner, whereas bevacizumab exerted no effect. Both drugs were detected inside early endosomes within the UM cells, with the stronger and sustained colocalization of ranibizumab. Our results therefore demonstrated the more potent and persistent suppressive activity of ranibizumab on the UM cells, possibly due to its higher level of uptake and prolonged intracellular retention. Further research on the endosome dynamics in UM cells might provide valuable insight into the response of these heterogenous tumors to therapeutic antibodies. View Full-Text
Keywords: uveal melanoma; VEGF-A; angiogenesis; bevacizumab; ranibizumab uveal melanoma; VEGF-A; angiogenesis; bevacizumab; ranibizumab
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Tura, A.; Pawlik, V.E.; Rudolf, M.; Ernesti, J.S.; Stutzer, J.-N.; Grisanti, S.; Ranjbar, M. Uptake of Ranibizumab but Not Bevacizumab into Uveal Melanoma Cells Correlates with a Sustained Decline in VEGF-A Levels and Metastatic Activities. Cancers 2019, 11, 868.

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