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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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Tumor growth after bevacizumab treatment. After placement of B16F10 melanoma cells in the eye of C57Bl/6 mice, bevacizumab was injected intraocularly to try to inhibit intraocular tumor growth. Following three bevacizumab injections on days 2, 6, and 10, a significant acceleration of intraocular tumor growth occurred compared to the control group (AVA1 versus control p=0.007, and AVA10 versus control p=0.06). Growth was recorded as the percentage of anterior chamber occupied with tumor, and mice were sacrificed when the tumor occupied 80%–100% of the anterior chamber. The curves are the pooled data from two experiments, with 14 mice in each of the three groups. AVA1=equivalent human dose: 2 μg/4 µl; AVA10=10 times the equivalent human dose: 20 μg/4 μl; CO=control group: 4 µl mock PBS injection.
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f1: Tumor growth after bevacizumab treatment. After placement of B16F10 melanoma cells in the eye of C57Bl/6 mice, bevacizumab was injected intraocularly to try to inhibit intraocular tumor growth. Following three bevacizumab injections on days 2, 6, and 10, a significant acceleration of intraocular tumor growth occurred compared to the control group (AVA1 versus control p=0.007, and AVA10 versus control p=0.06). Growth was recorded as the percentage of anterior chamber occupied with tumor, and mice were sacrificed when the tumor occupied 80%–100% of the anterior chamber. The curves are the pooled data from two experiments, with 14 mice in each of the three groups. AVA1=equivalent human dose: 2 μg/4 µl; AVA10=10 times the equivalent human dose: 20 μg/4 μl; CO=control group: 4 µl mock PBS injection.

Mentions: As VEGF-A inhibitors are being used to treat many different types of cancer metastases, we wondered whether they can be used to inhibit intraocular tumor growth. After intraocular inoculation of B16F10 melanoma cells into the anterior chamber of C57Bl/6 mice, two different doses of bevacizumab or medium were injected intraocularly on days 2, 6, and 10. Each group consisted of seven mice, and the experiment was performed twice. A summary of the results of the two experiments is shown in Figure 1. Whereas inhibition of tumor and vessel growth was expected, an acceleration of intraocular tumor growth was observed in eyes treated with both doses of bevacizumab. Treated mice had to be sacrificed earlier because the tumor started to protrude through the cornea. During the experiment, several anterior chamber and tumor hemorrhages were observed in the eyes that had been treated with bevacizumab but not in untreated eyes (Figure 2).


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)

Tumor growth after bevacizumab treatment. After placement of B16F10 melanoma cells in the eye of C57Bl/6 mice, bevacizumab was injected intraocularly to try to inhibit intraocular tumor growth. Following three bevacizumab injections on days 2, 6, and 10, a significant acceleration of intraocular tumor growth occurred compared to the control group (AVA1 versus control p=0.007, and AVA10 versus control p=0.06). Growth was recorded as the percentage of anterior chamber occupied with tumor, and mice were sacrificed when the tumor occupied 80%–100% of the anterior chamber. The curves are the pooled data from two experiments, with 14 mice in each of the three groups. AVA1=equivalent human dose: 2 μg/4 µl; AVA10=10 times the equivalent human dose: 20 μg/4 μl; CO=control group: 4 µl mock PBS injection.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Tumor growth after bevacizumab treatment. After placement of B16F10 melanoma cells in the eye of C57Bl/6 mice, bevacizumab was injected intraocularly to try to inhibit intraocular tumor growth. Following three bevacizumab injections on days 2, 6, and 10, a significant acceleration of intraocular tumor growth occurred compared to the control group (AVA1 versus control p=0.007, and AVA10 versus control p=0.06). Growth was recorded as the percentage of anterior chamber occupied with tumor, and mice were sacrificed when the tumor occupied 80%–100% of the anterior chamber. The curves are the pooled data from two experiments, with 14 mice in each of the three groups. AVA1=equivalent human dose: 2 μg/4 µl; AVA10=10 times the equivalent human dose: 20 μg/4 μl; CO=control group: 4 µl mock PBS injection.
Mentions: As VEGF-A inhibitors are being used to treat many different types of cancer metastases, we wondered whether they can be used to inhibit intraocular tumor growth. After intraocular inoculation of B16F10 melanoma cells into the anterior chamber of C57Bl/6 mice, two different doses of bevacizumab or medium were injected intraocularly on days 2, 6, and 10. Each group consisted of seven mice, and the experiment was performed twice. A summary of the results of the two experiments is shown in Figure 1. Whereas inhibition of tumor and vessel growth was expected, an acceleration of intraocular tumor growth was observed in eyes treated with both doses of bevacizumab. Treated mice had to be sacrificed earlier because the tumor started to protrude through the cornea. During the experiment, several anterior chamber and tumor hemorrhages were observed in the eyes that had been treated with bevacizumab but not in untreated eyes (Figure 2).

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