Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma.
To evaluate the inhibitory effects of aflibercept on the growth and subretinal invasion of retinoblastoma.



Xenotransplantation and orthotopic mouse models were created by injecting Y-79 cells subcutaneously and intravitreally, respectively. After induction of retinoblastoma, animals were intraperitoneally injected with aflibercept (25 mg/kg body weight) or saline twice a week for 3 weeks. Tumor size was measured weekly and compared between the two groups. At 4 weeks, animals were sacrificed and an immunohistochemical examination was conducted to compare the microvascular density and degree of apoptosis between groups. In addition, the degree of choroidal invasion was also analyzed in the orthotopic xenotransplantation model. A co-culture system of Y-79 or WERI-Rb-1 cells and human umbilical vein endothelial cells (HUVECs) was used for in vitro experiments, and the anti-angiogenic effect of aflibercept was evaluated by analyzing cell numbers.



In the Y-79 xenotransplantation model, aflibercept treatment significantly inhibited tumor growth at 4 weeks versus baseline compared with saline-injected mice (188.53 ± 118.53 mm3vs. 747.87 ± 118.83 mm3, respectively, P < 0.001). Tumors isolated from aflibercept-treated mice contained fewer blood vessels (8.59 % ± 7.60 % vs. 14.91 % ± 4.53 %, respectively, P < 0.05) and an increased number of apoptotic cells (15.10 ± 9.13 vs. 4.44 ± 2.24, respectively, P < 0.05). In the orthotopic model, the degree of subretinal invasion of tumor cells was significantly reduced after aflibercept treatment (0.07 ± 0.06 vs. 0.15 ± 0.10, P < 0.05). And addition of aflibercept to co-cultures of HUVECs and Y-79, WERI-Rb-1 cells significantly reduced HUVEC proliferation.



Aflibercept reduced retinoblastoma angiogenesis in association with a significant reduction in tumor growth and invasion. These findings suggest that aflibercept could be used in an adjuvant role together with systemic chemotherapy to reduce tumor size and angiogenesis in retinoblastoma.
Department of Ophthalmology, Chungbuk National University College of Medicine, Cheongju, Korea.
Dong Yoon
DY
Kim
Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
Jeong A
JA
Choi
Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.|Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jae-Young
JY
Koh
Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, Songpa-gu, Seoul, Korea. yhyoon@amc.seoul.kr.
Young Hee
YH
Yoon
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D009361:Neoplasm Invasiveness; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D019572:Retinal Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D012175:Retinoblastoma / Q000098:blood supply / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor
Aflibercept; Choroidal invasion; Retinoblastoma; Treatment