Bevacizumab and intraocular tumors: an intriguing paradox.
OBJECTIVE
Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor-A (VEGF-A), was originally developed as an anti-tumor treatment. In ocular oncology, it is being used to treat macular edema due to radiation retinopathy, but it may also be useful for the treatment of primary uveal melanoma (UM) or its metastases. We determined the effect of bevacizumab on the growth of B16F10 cells inside the eye and on B16F10 and UM cells cultured in vitro.


METHODS
B16F10 melanoma cells were placed into the anterior chamber of the eye of C57Bl/6 mice and tumor growth was monitored after injection of different doses of bevacizumab or mock injection. In addition, the effect of bevacizumab on in vitro growth of B16F10 and human UM cells and on the expression of VEGF-A, GLUT-1, and HIF-1α was evaluated.


RESULTS
Following intraocular injection of bevacizumab into murine B16 tumor-containing eyes, an acceleration of tumor growth was observed, with the occurrence of anterior chamber hemorrhages. Bevacizumab did not affect proliferation of B16F10 cells in vitro, while it inhibited UM cell proliferation. Expression analysis demonstrated that addition of bevacizumab under hypoxic conditions induced VEGF-A, GLUT-1 and HIF-1α in B16F10 cells as well as in UM cell lines and two of four primary UM tumor cultures.


CONCLUSIONS
In contrast with expectations, intraocular injection of bevacizumab stimulated B16F10 melanoma growth in murine eyes. In vitro exposure of B16 and human UM cells to bevacizumab led to paradoxical VEGF-A upregulation. The use of VEGF inhibitors for treatment of macular edema (due to radiation retinopathy) after irradiation of UM should be considered carefully, because of the possible adverse effects on residual UM cells.
Department of Ophthalmology, LUMC, Leiden, the Netherlands. m.el_filali@lumc.nl
Mariam
M
el Filali
Long V
LV
Ly
Gregorius P M
GP
Luyten
Mieke
M
Versluis
Hans E
HE
Grossniklaus
Pieter A
PA
van der Velden
Martine J
MJ
Jager
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000068258:Bevacizumab; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005130:Eye Hemorrhage / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005134:Eye Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D056965:Injections, Intraocular; D008297:Male; D008545:Melanoma / Q000473:pathology*; D008546:Melanoma, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017211:Treatment Failure; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D014604:Uveal Neoplasms / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000098943:Uveal Melanoma
D061067:Antibodies, Monoclonal, Humanized; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495678:Slc2a1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab