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BC Hayden, TG Murray, JR Gaitan, D Raja, EM Escalona, E Hernandez, N Cicciarelli, JJ Windle; Time Course Dependent Apoptosis Following Subconjunctival Carboplatin Therapy in the Treatment of Murine Transgenic Retinoblastoma . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2593.
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Purpose:To investigate the time course induction of apoptosis during serial subconjunctival carboplatin chemotherapy utilizing a murine transgenic model of retinoblastoma with established tumor burden. Methods:Thirty-two 10 week-old SV-40 T antigen positive mice received serial subconjunctival carboplatin injections at concentrations of 250µg/20µl every 72-hours to the right eye only. Eight eyes, serving as controls, received injections of balanced salt solution. Eyes were enucleated 24 hours after the first, fourth or sixth injection (n=8 eyes per treatment group). Treated and control eyes were obtained, fixed in formalin, paraffin embedded and serially sectioned. Samples were stained and analyzed using H&E and TACS Blue and the 3’ overhang ligand technique to detect tumor control and apoptotic cell death. Results:Time course, dose dependent apoptosis is associated with retinoblastoma cell death following serial subconjunctival carboplatin delivery. Histopathologic examination of eyes treated with subconjunctival carboplatin demonstrated a 194% increase in the number of intratumoral apoptotic cells after a single injection (total dose 250µg) over control eyes. After four injections (total dose 1000µg) the increase over the control was enhanced to 377% (p=0.02). Tumor size reduction in carboplatin treated eyes was noted in a time-dependent fashion. Eyes enucleated after the fourth and sixth injections exhibited 47% and 77% decreases respectively in tumor volume compared with untreated controls (p< 0.04). Conclusion:Apoptosis appears to be a mechanism of cell death in prolonged sustained subconjunctival delivery of carboplatin in this murine model of retinoblastoma. Intratumoral apoptosis increases with serial dose delivery, resulting in decreased tumor size over time. These data may provide insight into apoptosis and optimal dose scheduling, maximizing retinoblastoma cell destruction and tumor control in the management of pediatric intraocular retinoblastoma.
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