Treatment of Transgenic Murine Retinoblastoma With 4–Iodo–3–Nitrobenzamide (INO2BA), a Novel Chemotherapeutic Agent

Abstract

Abstract: : 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.

Keywords: tumors • retinoblastoma • drug toxicity/drug effects