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Patrick T. Logan, Shriya Hari, Matthew Balazsi, Dominique F de Souza, Claudia Martins, Miguel N. Burnier, Jr.; Bevacizumab In Combination With The Downregulation Of CCL3 Inhibits The Functional Dynamics Of Uveal Melanoma Cell Lines. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3393.
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Bevacizmuab is an anti-angiogenic agent that has been used for the treatment of a variety of malignant tumors and conditions in which aberrant vessel growth is implicated. Recent studies have shown that the ocular administration of bevacizumab results in the upregulation of several cytokines. The purpose of this study was to investigate if bevacizumab treatment in uveal melanoma cell lines significantly upregulated any of these common cytokines. The efficacy of bevacizumab in uveal melanoma cell lines when inhibiting one selected upregulated cytokine was also evaluated.
Three uveal melanoma cell lines (92.1, OCM-1, UW-1) were cultured for 24 hours in serum-free media with or without 100ug/ml of bevacizumab. The supernatant from the control and experimental conditions was assayed for the expression of 20 cytokines using a multiplex sandwich-ELISA technique. One consistently upregulated cytokine (CCL3) was selected and knocked down using siRNA. Migratory and proliferative abilities of each cell line were measured, under the following conditions: bevacizumab, CCL3 siRNA, bevacizumab with CCL3 siRNA, and control. A Student’s t-test was performed for all comparisons and a P-value of < 0.05 was considered significant.
MMP-9 and CCL3 were significantly upregulated in all cell lines after bevacizumab treatment. CCL3 was selected for inhibition, as it is an upstream regulator of MMP-9 expression. Bevacizumab treatment caused a significant reduction in the proliferation of one cell line (92.1), while CCL3 siRNA resulted in significant decreases in the proliferation of all cell lines. Combination treatment (CCL3 siRNA + bevacizumab) decreased the proliferation of all cell lines greater than either treatment alone; this difference was significant for one cell line (92.1) when compared to CCL3 siRNA treatment alone, and for all cell lines treated with bevacizumab. With respect to migration, CCL3 siRNA combined with bevacizumab significantly reduced all cell lines, which was not accomplished using either treatment alone.
While bevacizumab decreased some of the functional abilities of uveal melanoma cell lines, it also upregulated potent cytokines, such as CCL3. The combination of CCL3 knockdown and bevacizumab yielded benefits not seen with bevacizumab monotherapy. This combination therapy should be examined further to determine possible clinical relevance as a treatment for uveal melanoma.
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