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J. Tsui, K.R. Van Quill, C.L. Dalgard, L. Lee, H.E. Grossniklaus, H.F. Edelhauser, J.M. O'Brien; Subconjuctival Topotecan In Fibrin Sealant In The Treatment Of Transgenic Murine Retinoblastoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2289.
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© ARVO (1962-2015); The Authors (2016-present)
Topotecan is a topoisomerase I inhibitor that induces cytotoxic effects in retinoblastoma cells in vitro and reduces tumor burden in children with neurogenic tumors. We recently reported that subconjunctival injection of carboplatin in fibrin sealant (FS) is effective in the treatment of retinoblastoma in transgenic mice. In this study, we evaluated the efficacy of subconjunctival topotecan in fibrin sealant in the treatment of transgenic murine retinoblastoma.
Y79 human retinoblastoma cells were seeded into 96–well microtitre plates (10,000 cells/well) and treated with topotecan, topotecan in FS, or vehicle control. At 72 hours post–treatment, growth inhibitory effects were quantified by WST–1 Cell Proliferation Assay (Roche). A toxicity study was performed in 8 groups of 3 mice treated bilaterally with a single 30 µL subconjunctival injection of topotecan in FS at concentrations up to 3.2 mg/mL. Upon completion of this study, 2 additional mice were treated bilaterally with 3.2mg/mL of topotecan in fibrin sealant to confirm the safety of this dose. A therapeutic study was then performed in 2 groups of 20 ten–week–old mice treated in the right eye with a single 30 µL injection of topotecan in FS (3.2 mg/ml) or FS only. Mice were sacrificed on day 22 after treatment. Eyes were enucleated, formalin–fixed, paraffin–embedded, and serially sectioned. Ocular tumor burden was quantified by histopathologic analysis.
The IC50 of topotecan in Y79 cells was 30 nM after 72 hours. In the in vivo toxicity study, no histopathologic evidence of ocular toxicity was observed in any dose group. Among mice treated with the highest dose of topotecan in FS (3.2mg/mL), eyelid alopecia was observed in 2/10 eyes and enophthalmos was observed in 1/10 eyes. Results of the therapeutic study are forthcoming and will reveal whether topotecan in FS at this dose can control tumor growth in murine retinoblastoma.
Topotecan induces potent cytotoxic effects in retinoblastoma cell lines and is well tolerated in mice when administered subconjunctivally in FS at doses as high as 3.2 mg/mL (= 0.1 mg total dose). If this modality is effective in the treatment of transgenic murine retinoblastoma, we would consider proposing a clinical trial in retinoblastoma patients.
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