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Nathalie Cassoux, franck Assayag, Olfa Chouchane-Mlik, fariba Nemati, Aurelie Thuleau, Jean-Jacques Fontaine, Isabelle Aets, Laurence Desjardins, francois Doz, Didier Decaudin; Intraocular Treatments of a New Orthotopic Primary Human Retinoblastoma Xenograft. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6869.
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The treatment retinoblastoma could require enucleation in unfavorable prognostic disease. In order to allow pharmacological assessment of innovative intraocular treatments in more relevant and predictive models, we have developed preclinical orthotopic primary retinoblastoma (Rb) models xenografted into SCID immunodeficient mice
Orthotopic models of human Rb have been developed from two panels of 3 subcutaneous xenografts model (RB102, RB111, and RB200) previously established and characterized in the laboratory (Aerts et al 2010). One of them, RB200, was used for intraocular therapeutic experiment. Mice bearing xenografts were sacrificed and tumors were dissected to obtain a suspension of fresh tumor cells at a concentration of 8000 cells/μl in DMEM serum-free medium. Under intraperitoneal anesthesia, 2μl of cell suspension was injected into the subretinal space of the right eye for 4 groups of mice using a 32G needle via a Hamilton syringe. Each group was constituted by 6 SCID mice. After sub-retinal injection, ophthalmic examination of the mice was performed weekly. When tumor cells started to invade vitreal cavity, the mice were treated by intravitreal injection (one injection/week for 4 weeks) of BSS (balanced salt solution) (control), bevacizumab (25mg/kg), melphalan (500 μg/kg), and carboplatine (100μg/kg). Fifteen days after end of treatment, mice were sacrificed for pathological analyses.
All transplanted mice have developed a retinal tumor 6 weeks after subretinal tumor cell injection. In the control group, pathological analyses showed enormous tumors of undifferentiated Rb cells with massive infiltration of vitreous cavity and anterior chamber, and extrascleral extension in 4/6 mice. In the bevacizumab group, pathological analyses showed massive infiltration of the eye by Rb cells in 6/6 mice with extrascleral extension in 2/6 mice. In contrast, in the melphalan group, we have observed complete regression of the tumor in 2/6 mice. For the 4 remaining mice, pathological analyses showed the absence of vitreal cells and a reduction of the tumor mass of approximately 50% compared to the control group. Finally, in the carboplatine group, we have shown a complete regression of the tumour in 5/6 mice with a reduction of the tumour volume in the 6th mouse compared to the control group.
Using intraocular administration in an orthotopic xenografted Rb model, we have observed a high efficacy of carboplatin (83% of responses), intermediate efficacy of melphalan (33%), and no efficacy of bevacizumab (0%). Such experiment suggests that new therapies could therefore be tested in an intraocular setting alone or in combination with standard chemotherapies.
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