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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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Related in: MedlinePlus

Proliferation of UM cell lines after bevacizumab treatment. Proliferation of UM cell lines was measured by WST-1 assay after exposure to three different doses of bevacizumab during one, three or six days, under normoxic and hypoxic conditions. Cell density is expressed as absorbance (optical density, OD). A dose-dependent decrease of proliferation after treatment with bevacizumab occurs under hypoxic as well as normoxic conditions. AVA1=equivalent human dose: 1.25 mg/ 5.46 ml; AVA10=10 times the equivalent human dose: 12.5 mg/ 5.46 ml; AVA20=20 times the equivalent human dose: 25 mg/ 5.46 ml; CO=control group: culture medium.
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f6: Proliferation of UM cell lines after bevacizumab treatment. Proliferation of UM cell lines was measured by WST-1 assay after exposure to three different doses of bevacizumab during one, three or six days, under normoxic and hypoxic conditions. Cell density is expressed as absorbance (optical density, OD). A dose-dependent decrease of proliferation after treatment with bevacizumab occurs under hypoxic as well as normoxic conditions. AVA1=equivalent human dose: 1.25 mg/ 5.46 ml; AVA10=10 times the equivalent human dose: 12.5 mg/ 5.46 ml; AVA20=20 times the equivalent human dose: 25 mg/ 5.46 ml; CO=control group: culture medium.

Mentions: To determine whether the mechanism observed in murine B16F10 cells was relevant to the human situation, the in vitro tests were repeated using human UM cell lines and primary cell cultures. Following treatment with bevacizumab, human UM cell lines showed a dose-dependent decrease of proliferation under normoxic as well as hypoxic culture conditions (Figure 6). Four primary tumor cell cultures displayed a greater variability: in two cultures inhibition of proliferation was observed while two other cell cultures appeared resistant and did not show an effect (data not shown).


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 UM cell lines after bevacizumab treatment. Proliferation of UM cell lines was measured by WST-1 assay after exposure to three different doses of bevacizumab during one, three or six days, under normoxic and hypoxic conditions. Cell density is expressed as absorbance (optical density, OD). A dose-dependent decrease of proliferation after treatment with bevacizumab occurs under hypoxic as well as normoxic conditions. AVA1=equivalent human dose: 1.25 mg/ 5.46 ml; AVA10=10 times the equivalent human dose: 12.5 mg/ 5.46 ml; AVA20=20 times the equivalent human dose: 25 mg/ 5.46 ml; CO=control group: culture medium.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Proliferation of UM cell lines after bevacizumab treatment. Proliferation of UM cell lines was measured by WST-1 assay after exposure to three different doses of bevacizumab during one, three or six days, under normoxic and hypoxic conditions. Cell density is expressed as absorbance (optical density, OD). A dose-dependent decrease of proliferation after treatment with bevacizumab occurs under hypoxic as well as normoxic conditions. AVA1=equivalent human dose: 1.25 mg/ 5.46 ml; AVA10=10 times the equivalent human dose: 12.5 mg/ 5.46 ml; AVA20=20 times the equivalent human dose: 25 mg/ 5.46 ml; CO=control group: culture medium.
Mentions: To determine whether the mechanism observed in murine B16F10 cells was relevant to the human situation, the in vitro tests were repeated using human UM cell lines and primary cell cultures. Following treatment with bevacizumab, human UM cell lines showed a dose-dependent decrease of proliferation under normoxic as well as hypoxic culture conditions (Figure 6). Four primary tumor cell cultures displayed a greater variability: in two cultures inhibition of proliferation was observed while two other cell cultures appeared resistant and did not show an effect (data not shown).

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