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N.A. Laurie, S.L. Donovan, M.A. Dyer; Targeting the p53 Pathway in Retinoblastoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2814.
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It is well established that retinoblastomas are particularly sensitive to DNA damage mediated by radiation or pharmacological agents. Unfortunately, radiation therapy is no longer a front–line therapy for retinoblastoma due to the risk of secondary malignancies induced by DNA damage outside of the ocular field. However, pharmacological agents targeted to the p53 DNA damage response pathway may prove useful for the treatment of retinoblastoma.
The purpose of this research project is to test whether inducing the p53 pathway in human retinoblastoma is an effective way to target chemotherapy and improve the ocular salvage rate for children with bilateral late–stage retinoblastoma.
We used two different approaches to induce the p53 pathway with pharmacological agents in retinoblastoma cells. The first approach utilizes high concentrations of the topoisomerase inhibitor topotecan. The second approach utilizes a small molecule that induces the p53 pathway called nutlin–3. Human retinoblastoma cell lines (Weri1, Y79, Rbl355) were tested as well as a positive control myeloid leukemia cell line (ML–1) and a negative control mouse retinoblastoma cell line (SJ Rbl–8) that is p53 deficient.
We report here that the p53 pathway is readily induced in all of the retinoblastoma cell lines following 5 Gy of ionizing radiation or topotecan treatment or nutlin–3 exposure. Cells undergo cell cycle arrest and/or cell death. The p53 deficient cells (SJ Rbl–8) showed no effect of these treatments. Using a p53 siRNA we demonstrated that the effect was p53 dependent. Using preclinical retinoblastoma models developed in our lab, we tested the efficacy of these drugs in vivo.
Our data suggest that targeting the p53 pathway with pharmacological agents may be very useful for the treatment of retinoblastoma. Subconjunctival application of topotecan or nutlin–3 may provide sufficient intravitreal concentrations to achieve the effects we see in culture. These are the first data showing that targeted chemotherapy may be effective for retinoblastoma treatment.
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