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Bevacizumab and intraocular tumors: an intriguing paradox.

el Filali M, Ly LV, Luyten GP, Versluis M, Grossniklaus HE, van der Velden PA, Jager MJ - Mol. Vis. (2012)

Bottom Line: We determined the effect of bevacizumab on the growth of B16F10 cells inside the eye and on B16F10 and UM cells cultured in vitro.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.Bevacizumab did not affect proliferation of B16F10 cells in vitro, while it inhibited UM cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands. m.el_filali@lumc.nl

ABSTRACT

Purpose: 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.

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Proliferation of B16F10 cells after bevacizumab treatment. Bevacizumab was added to B16F10 cells in vitro under normoxic (top) and hypoxic (bottom) circumstances and proliferation was measured by WST-1 assay on days one, two and three after addition of bevacizumab. Cell density is expressed in absorbance (optical density, OD). A high dose of bevacizumab inhibited cell growth under hypoxic conditions.
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f3: Proliferation of B16F10 cells after bevacizumab treatment. Bevacizumab was added to B16F10 cells in vitro under normoxic (top) and hypoxic (bottom) circumstances and proliferation was measured by WST-1 assay on days one, two and three after addition of bevacizumab. Cell density is expressed in absorbance (optical density, OD). A high dose of bevacizumab inhibited cell growth under hypoxic conditions.

Mentions: As the in vivo results showed the opposite effects of what was expected, we studied the effect of bevacizumab on tumor cell proliferation under normoxia and hypoxia. Addition of bevacizumab to B16F10 cells in vitro did not effect proliferation of tumor cells cultured in normoxic conditions, while a dose-dependent decrease in proliferation was noticed after treatment with bevacizumab under normoxic conditions (Figure 3).


Bevacizumab and intraocular tumors: an intriguing paradox.

el Filali M, Ly LV, Luyten GP, Versluis M, Grossniklaus HE, van der Velden PA, Jager MJ - Mol. Vis. (2012)

Proliferation of B16F10 cells after bevacizumab treatment. Bevacizumab was added to B16F10 cells in vitro under normoxic (top) and hypoxic (bottom) circumstances and proliferation was measured by WST-1 assay on days one, two and three after addition of bevacizumab. Cell density is expressed in absorbance (optical density, OD). A high dose of bevacizumab inhibited cell growth under hypoxic conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472924&req=5

f3: Proliferation of B16F10 cells after bevacizumab treatment. Bevacizumab was added to B16F10 cells in vitro under normoxic (top) and hypoxic (bottom) circumstances and proliferation was measured by WST-1 assay on days one, two and three after addition of bevacizumab. Cell density is expressed in absorbance (optical density, OD). A high dose of bevacizumab inhibited cell growth under hypoxic conditions.
Mentions: As the in vivo results showed the opposite effects of what was expected, we studied the effect of bevacizumab on tumor cell proliferation under normoxia and hypoxia. Addition of bevacizumab to B16F10 cells in vitro did not effect proliferation of tumor cells cultured in normoxic conditions, while a dose-dependent decrease in proliferation was noticed after treatment with bevacizumab under normoxic conditions (Figure 3).

Bottom Line: We determined the effect of bevacizumab on the growth of B16F10 cells inside the eye and on B16F10 and UM cells cultured in vitro.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.Bevacizumab did not affect proliferation of B16F10 cells in vitro, while it inhibited UM cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands. m.el_filali@lumc.nl

ABSTRACT

Purpose: 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.

Show MeSH
Related in: MedlinePlus