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K. Ramonas, J. Qi, C.T. Tong, S.A. Howard, K.R. Van Quill, N. Green, H.E. Grossniklaus, J.M. O'Brien; Treatment of Transgenic Murine Retinoblastoma With 4–Iodo–3–Nitrobenzamide (INO2BA), a Novel Chemotherapeutic Agent . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3422.
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Purpose:INO2BA is a non–covalently binding inhibitory ligand of poly ADP–ribose polymerase I (PARP), a pleiotropic nuclear enzyme involved in DNA repair and regulation of gene expression. This agent has demonstrated cytotoxicity in a variety of tumor cell lines, including prostate, breast, ovarian, lung, pancreatic, and leukemia. In this study, we evaluated the in vivo efficacy of systemic INO2BA in the treatment of transgenic murine retinoblastoma. Methods: Two groups of 25 10–week–old LHß–Tag transgenic mice were treated with intraperitoneal injections of either INO2BA or vehicle control. Group 1 (treated group) received one injection of buthionine sulfoximine (BSO, 450 mg/kg, q am) and INO2BA (25 mg/kg, q pm), 5 days per week for six weeks. BSO is a glutathione synthesis inhibitor that has been shown to increase toxicity of INO2BA in tumor cells. Group 2 (control group) received vehicle only on the same treatment schedule. Mice were sacrificed on day 43. Eyes were serially sectioned and ocular tumor burden was quantified by histopathologic analysis. A t–test was used to analyze differences in mean tumor burden between treatment and control groups. Results: Mean ocular tumor burden per mouse was 209,989 +/– 144,448 square pixels in the treatment group versus 175,622 +/– 208,679 square pixels in the control group. There was no statistically significant difference in ocular tumor burden between INO2BA treated and control mice (p < 0.54). Conclusions: Systemic delivery of INO2BA is not effective in the treatment of transgenic murine retinoblastoma. Despite a novel mechanism of action and demonstrated tumoricidal activity in other tumor cell lines investigated to date, INO2BA did not significantly decrease tumor burden in this murine model of retinoblastoma.
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