Abstract 3574: Study of the anti-glioma properties of the nitrone OKN007 by magnetic resonance imaging
Authors: Philippe Garteiser, Ting He, Sabrina Doblas, Nataliya Smith, Margaret Wang, Benjamin P. Pittmann, Debbie Saunders, Jessica Hoyle, David Gillespie, Andrea Schwager, Randy Jensen, Robert A. Floyd, Rheal A. Towner
Journal: Cancer Research (2010)

Abstract The nitrone compound OKN007, a disulfonated derivative of phenyl-tert-butylnitrone, is known to have anti-glioma properties in a rat C6 glioma model. In this study, the effect of OKN007 was studied using three orthotopically implanted glioma cell lines in the rat. In addition, some preliminary data investigating the involvement of the iNOS anti-inflammatory pathway in the anti-glioma activity of OKN007 is provided. The effect OKN007 on glioma was assessed by magnetic resonance imaging of rats orthotopically implanted with 10^6 C6, F98 or RG2 cells. Tumor volumes and growth rates were determined with T2-weighted imaging. The inflammatory edema and other properties of the glioma were assessed with diffusion-weighted imaging. Finally, tumor perfusion rates were measured by arterial spin labeling. The drug (25-30μmol/(kg·day)) was administered 15 days after tumor cell implantation in the drinking water or by a continuous intravenous perfusion, with appropriate saline controls. The expression levels of iNOS were measured using western blots. In addition, C6 cells stably transfected with an iNOS shRNA silencing plasmid were also implanted in an effort to delineate the involvement of this mediator in tumor growth. OKN007 was found to have an effect on the growth of C6 gliomas both when administered in the drinking water or intravenously. Doubling times were slower when OKN007 was administered orally (7.9±1.2 days, versus 2.7±0.3 days for the controls), but not when administered intravenously, although the latter route was tested on a smaller cohort. The drug affected the perfusion and diffusion profiles of the C6 tumors for both types of administration. In the C6 model, administration of the drug brought perfusion and diffusion values closer to those found in normal brain. Both administration routes had an effect on the tumor volume at day 35. In the RG2 model, OKN007 increased the doubling times of the tumors, although more controls are required to reach statistical significance. The effects of OKN007 on the F98 glioma cell line are currently under investigation. Western blot analyses on the C6 model revealed that in treated animals the iNOS levels, although higher than in the normal brain, were lower than in non treated tumors. Finally, preliminary evidence of the requirement of iNOS for tumor development in the context of orthotopic implantation of the tumor cells was obtained using the iNOS shRNA-transfected C6 cell line. In conclusion, OKN007 was found to have a suppressive effect on the growth of C6 rat glioma, with drinking water administration yielding the best results. The nitrone may also have a therapeutic potential for RG2 and F98 models. The precise mechanisms of action of OKN007 are still unknown, but may involve an interference with iNOS-mediated inflammation. Together with the established safety of this nitrone for humans, our results indicate that OKN007 may be a promising anti glioma agent for clinical use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3574.