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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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mRNA expression of UM cell lines after bevacizumab treatment mRNA expression was measured with qPCR after exposure to different doses of bevacizumab under hypoxic conditions for 24 h. Expression is shown in normalized fold. Treatment with bevacizumab induced VEGF-A and GLUT-1 mRNA. 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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f7: mRNA expression of UM cell lines after bevacizumab treatment mRNA expression was measured with qPCR after exposure to different doses of bevacizumab under hypoxic conditions for 24 h. Expression is shown in normalized fold. Treatment with bevacizumab induced VEGF-A and GLUT-1 mRNA. 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: Treatment of two UM cell lines with bevacizumab under hypoxic conditions led to an induction of VEGF-A mRNA (Figure 7). Exposure of UM cells to bevacizumab at normal oxygen levels showed the same trend, but was less substantial (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)

mRNA expression of UM cell lines after bevacizumab treatment mRNA expression was measured with qPCR after exposure to different doses of bevacizumab under hypoxic conditions for 24 h. Expression is shown in normalized fold. Treatment with bevacizumab induced VEGF-A and GLUT-1 mRNA. 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

f7: mRNA expression of UM cell lines after bevacizumab treatment mRNA expression was measured with qPCR after exposure to different doses of bevacizumab under hypoxic conditions for 24 h. Expression is shown in normalized fold. Treatment with bevacizumab induced VEGF-A and GLUT-1 mRNA. 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: Treatment of two UM cell lines with bevacizumab under hypoxic conditions led to an induction of VEGF-A mRNA (Figure 7). Exposure of UM cells to bevacizumab at normal oxygen levels showed the same trend, but was less substantial (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