Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture.
OBJECTIVE
To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture.


METHODS
Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death.


RESULTS
Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses.


CONCLUSIONS
At clinical doses, neither ranibizumab nor aflibercept produced evidence of mitochondrial toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses.
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, California, USA.
Deepika
http://orcid.org/0000-0002-3722-6711
D
Malik
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, California, USA Department of Ophthalmology, El-Minya University, El-Minya, Egypt.
Mohamed
M
Tarek
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, California, USA.
Javier
J
Caceres del Carpio
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, California, USA.
Claudio
C
Ramirez
Retina-vitreous Associates Medical Group, Los Angeles, California, USA.
David
D
Boyer
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, California, USA.
M Cristina
MC
Kenney
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, California, USA.
Baruch D
BD
Kuppermann
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000068258:Bevacizumab; D002102:Cadaver; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012016:Reference Values; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab
Angiogenesis; Macula; Treatment Medical