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C. L. Dalgard, J. Yang, K. van Quill, J. M. O'Brien; Potent Antitumor Activity of Histone Deacetylase Inhibitors in Human Retinoblastoma Cells and Murine Transgenic Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1599.
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© ARVO (1962-2015); The Authors (2016-present)
Retinoblastoma is a pediatric cancer and blinding eye disease. Combination chemotherapy is the current firstline therapy for larger RB tumors. Histone deacetylase (HDAC) inhibitors have demonstrated efficacy for the treatment of various human cancers. In this study, we systematically characterized the potential utility of HDAC inhibitors for the treatment of retinoblastoma.
Retinoblastoma cells lines (Y79, WERI-Rb1, Rb143) and human primary retinoblastoma cells (Rb641) were treated with increasing concentrations of HDAC inhibitors (TSA, SAHA, MS-275) in a cell viability assay. Analysis of cell cycle status, caspase-3/7 activity, and annexin V binding were performed in these cells after HDAC inhibitor treatment. Additionally, we performed cell viability assay using HDAC inhibitors in combination with one of the standard agents in RB therapy (carboplatin, etoposide, or vincristine). A single intraperitoneal injection of up to 4 mg MS-275 was used to study the drug’s ability to cross the blood-retinal barrier. We tested the therapeutic effects of MS-275 in a transgenic murine model of retinoblastoma by adminstration of 20 mg/kg MS-275 intraperitoneally every other day for 21 days.
Treatment of human retinoblastoma cells with various HDAC inhibitors significantly decreased cell viability in a concentration dependent manner. HDAC inhibitor treatment also resulted in G1 cell cycle arrest and apoptotic cell death as demonstrated by increased caspase-3/7 activity and annexin V binding. In vitro cell viability assays using HDAC inhibitors in combination with one of the standard agents in RB therapy displayed additive or synergistic cytotoxic effects. An increase in the level of acetylated histone H3 protein from whole eye extracts confirmed intraocular penetration of MS-275 after systemic treatment. Retinoblastoma tumor burden was significantly reduced in animals treated with 20 mg/kg MS-275 intraperitoneally every other day for 21 days, relative to vehicle treated controls.
This study identifies MS-275 and other HDAC inhibitors as promising candidate agents for the treatment of retinoblastoma. MS-275 is currently in Phase I and II clinical trials for solid tumors and leukemia and thus, promising data from this and other preclinical studies may quickly translate into clinical trials for the treatment of retinoblastoma.
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