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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

mRNA expression of UM cell cultures after bevacizumab treatment under hypoxic conditions. mRNA expression was measured with qPCR under hypoxic conditions and after 24 h of different doses bevacizumab treatment. Expression is demonstrated in normalized fold. Two cell cultures show a clear induction of VEGF-A expression after treatment with bevacizumab (culture two and three). GLUT-1 expression in UM cell cultures corresponds to the VEGF-A expression (bottom); correlation coefficient 0.974, p=0.0002. 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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f8: mRNA expression of UM cell cultures after bevacizumab treatment under hypoxic conditions. mRNA expression was measured with qPCR under hypoxic conditions and after 24 h of different doses bevacizumab treatment. Expression is demonstrated in normalized fold. Two cell cultures show a clear induction of VEGF-A expression after treatment with bevacizumab (culture two and three). GLUT-1 expression in UM cell cultures corresponds to the VEGF-A expression (bottom); correlation coefficient 0.974, p=0.0002. 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: In primary UM cell cultures, the effect of bevacizumab on proliferation had been variable: in the two cell cultures which had shown reduced proliferation, bevacizumab induced VEGF-A expression (Figure 8) with a maximum fold increase of 3.36 and 2.48 (cultures two and three). The two other cultures which continued to proliferate in the presence of bevacizumab showed a high VEGF-A expression that was not affected by treatment.


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 cultures after bevacizumab treatment under hypoxic conditions. mRNA expression was measured with qPCR under hypoxic conditions and after 24 h of different doses bevacizumab treatment. Expression is demonstrated in normalized fold. Two cell cultures show a clear induction of VEGF-A expression after treatment with bevacizumab (culture two and three). GLUT-1 expression in UM cell cultures corresponds to the VEGF-A expression (bottom); correlation coefficient 0.974, p=0.0002. 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

f8: mRNA expression of UM cell cultures after bevacizumab treatment under hypoxic conditions. mRNA expression was measured with qPCR under hypoxic conditions and after 24 h of different doses bevacizumab treatment. Expression is demonstrated in normalized fold. Two cell cultures show a clear induction of VEGF-A expression after treatment with bevacizumab (culture two and three). GLUT-1 expression in UM cell cultures corresponds to the VEGF-A expression (bottom); correlation coefficient 0.974, p=0.0002. 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: In primary UM cell cultures, the effect of bevacizumab on proliferation had been variable: in the two cell cultures which had shown reduced proliferation, bevacizumab induced VEGF-A expression (Figure 8) with a maximum fold increase of 3.36 and 2.48 (cultures two and three). The two other cultures which continued to proliferate in the presence of bevacizumab showed a high VEGF-A expression that was not affected by treatment.

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