Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

Kim, Dong Yoon; Choi, Jeong A; Koh, Jae‐Young; Yoon, Young Hee

doi:10.1186/s13046-016-0451-7

Cited by 11 publications

(10 citation statements)

References 57 publications

(59 reference statements)

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“…Four weeks after the injection, mice were injected with either aflibercept (25 mg/kg) or saline intraperitoneally once a week for 4 weeks. [26][27][28][29][30][31][32] Body weights and blood glucose levels were measured at intervals of 1 and 2 weeks, respectively. In total, 220 mice were sacrificed for the experiment.…”

Section: Animalsmentioning

confidence: 99%

Aflibercept ameliorates retinal pericyte loss and restores perfusion in streptozotocin-induced diabetic mice

Seo¹,

Choi²,

Koh³

et al. 2020

BMJ Open Diab Res Care

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IntroductionAnti-vascular endothelial growth factor (VEGF) agents are used worldwide for advanced-stage diabetic retinopathy (DR). In contrast, apart from blood glucose control, there are no specific treatments that can limit the progression of early-stage DR that starts with pericyte loss and the destruction of the blood–retinal barrier. Here, we examined the efficacy of aflibercept, a potent anti-VEGF agent, against early-DR pathologies in a murine model of streptozotocin (STZ)-induced DR.Research design and methodsSTZ was intraperitoneally administered in 8-week-old C57BL/6N male mice. After 4 weeks, the mice were divided into aflibercept-treated and saline-treated groups. Eight weeks after the STZ injection, vascular permeability/leakage was measured with fluorescein angiography in live mice. At 4, 6, and 8 weeks after the STZ injection, the eyes were enucleated, flat-mounted, and stained for platelet-derived growth factor receptor-β to assess pericyte abundance, CD45 to assess leukocyte recruitment, and fluorescein isothiocyanate dextran to assess perfusion. VEGF levels were quantified in each group. The effects of aflibercept on pericyte number, perfusion status, and leukocyte recruitment/accumulation on mice with diabetes retina were evaluated.ResultsOur murine model successfully replicated the salient pathologies of DR such as pericytes loss, hyperpermeability, and perfusion blockage. Interestingly, numerous leukocytes and leukocyte clumps were found in diabetic retinal capillaries, especially in the non-perfused border area of the retina, suggesting a possible mechanism for non-perfusion and related pericyte damage. Treatment with aflibercept in mice with diabetes inhibited the upregulation of VEGF and the associated adhesion molecules while reducing the defects in perfusion. Aflibercept also attenuated pericyte loss in the diabetic retina.ConclusionVEGF inhibition through aflibercept treatment decreased leukocyte recruitment and aggregation, perfusion blockage, retinal hypoperfusion, and hyperpermeability in mice with diabetes and ultimately attenuated pericyte loss. Our findings suggest that anti-VEGF strategies may prove useful as possible therapies for limiting the progression of early-stage DR.

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Section: Animalsmentioning

confidence: 99%

Aflibercept ameliorates retinal pericyte loss and restores perfusion in streptozotocin-induced diabetic mice

Seo¹,

Choi²,

Koh³

et al. 2020

BMJ Open Diab Res Care

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“…Considering the limitation of our experimental technology and funding, we constructed a subcutaneous retinoblastoma model. 23 , 29 , 46 , 47 The microenvironment and its immune response greatly affect proliferation and survival of tumor. Subcutaneous environment vary greatly with intraocular space and retina tissue.…”

Section: Discussionmentioning

confidence: 99%

<p>Effect of miR-515-5p on Proliferation and Drug Sensitivity of Retinoblastoma Cells</p>

Yuan¹,

Yan²,

Tong³

2020

CMAR

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Background: Retinoblastoma (RB) is a common malignancy in children eyes. Aberrant microRNA (miR) expression is observed in many cancer cases. miR-515-5p is reported to be concerned with the course of many cancers. This study explores the role of miR-515-5p in proliferation and drug sensitivity of RB cells. Methods: Human RB cell lines (WERI-RB1, SO-RB50 and Y79) and human retinal pigment epithelial cell line ARPE-19 were utilized in this study. Drug-resistant cells SO-RB50/VCR and SO-RB50/CBP were constructed for the following experiments. The expressions of miR-515-5p and Notch1 in RB cells were detected. Notch1 was significantly upregulated in RB cells while miR-515-5p was notably downregulated. Then, the binding relationship between miR-515-5p and Notch1 was predicted and verified. Results: miR-515-5p negatively regulated Notch1 expression. In vitro and in vivo experiments revealed that overexpressed miR-515-5p inhibited RB cell proliferation and enhanced drug sensitivity. Functional rescue experiment suggested that miR-515-5p regulated RB cell proliferation and drug sensitivity via inhibiting Notch1 expression. Conclusion: It could be concluded that overexpressed miR-515-5p suppressed proliferation and drug resistance of RB cells by targeting Notch1 expression, indicating that miR-515-5p might constitute a promising therapy target for RB.

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“…RB, a malignant intraocular tumor known to be most common among children (21), is often associated with distant metastasis and can be fatal if left untreated (22). Chemotherapy with drugs, such as carboplatin, etoposide and vincristine along with local consolidation treatment is the primary treatment strategy for RB.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the therapeutic effects of lobaplatin and carboplatin on retinoblastoma in vitro and in vivo

et al. 2020

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Retinoblastoma (RB) is one of the most aggressive malignancies affecting infants and children. Platinum drugs are commonly used in the treatment of RB; however, their efficacy is often compromised by drug resistance and severe toxicity. The present study aimed to investigate and compare the toxicity and antitumor activity of the third-generation platinum drugs, carboplatin and lobaplatin, in vitro and in vivo. The Y79 RB cell line was treated with carboplatin or lobaplatin in vitro and then used to establish xenografts in immunodeficient nude mice in vivo; the effects of pharmacological doses of these drugs were then assessed. High concentrations of carboplatin and lobaplatin markedly inhibited Y79 RB cell proliferation in vitro. In addition, the lobaplatin group exhibited higher proportions of early-stage apoptotic cells than the carboplatin group, while no significant differences in the proportions of cells in the S phase were observed between the 2 groups, as shown by flow cytometry. Significant changes in the E2F1/Cdc25a/Cdk2 pathway in the RB cells were detected by RNA-seq following carboplatin or lobaplatin intervention. RT-qPCR, immunofluorescence and immunohistochemical analyses in vivo and in vitro demonstrated that the trends of drug-induced inhibition of tumor pathological changes may have been regulated through the E2F1/Cdc25a/Cdk2 pathway, and that lobaplatin was more effective than carboplatin in controlling tumors in vivo. On the whole, the findings of the present study demonstrate that lobaplatin is associated with lower cytotoxicity and exerts more prominent therapeutic effects than carboplatin on Y79 RB cells in vitro and in mice in vivo.

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Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

Cited by 11 publications

References 57 publications

Aflibercept ameliorates retinal pericyte loss and restores perfusion in streptozotocin-induced diabetic mice

Aflibercept ameliorates retinal pericyte loss and restores perfusion in streptozotocin-induced diabetic mice

<p>Effect of miR-515-5p on Proliferation and Drug Sensitivity of Retinoblastoma Cells</p>

Comparison of the therapeutic effects of lobaplatin and carboplatin on retinoblastoma in vitro and in vivo

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