Multiparametric assessment of the anti‐glioma properties of OKN007 by magnetic resonance imaging

Abstract

Purpose: To demonstrate that OKN007, a disulfonyl derivative of phenyl-tert-butyl nitrone (PBN), has anti-glioma activity in the clinically relevant C6 rat glioma model using multi-parametric magnetic resonance imaging.Materials and Methods: Twenty-one rats were intracerebrally implanted with C6 cells and administered OKN007 or kept as controls. Animals were monitored with MRI at 7 Tesla (T), using morphologic, diffusion-weighted and perfusion imaging, followed by histology and Western blots of angiogenesis and inflammatory markers.Results: OKN007 was found to decrease tumor volumes and increase survival. The glioma tissues of OKN007-treated rats were found to have longitudinal apparent diffusion coefficients (ADC z ) of 0.76 6 0.06 Â 10 À3 mm 2 /s, similar to the contralateral tissue and significantly smaller than untreated gliomas (0.97 6 0.13 Â 10 À3 mm 2 /s). They had higher perfusion rates (66 6 4 mL/100 gÁmin) than untreated gliomas (26 6 7 mL/100 gÁmin). All examined molecular markers were decreased in OKN007-treated rat gliomas, compared with elevated levels in untreated rats.Conclusion: MRI assessment was successfully used to monitor a decrease in tumor growth, and corresponding alterations in ADC and perfusion rates in rat C6 gliomas treated with the anti-glioma agent, OKN007.

Assessment of Rodent Glioma Models Using Magnetic Resonance Imaging Techniques

“…It was concluded from these studies that PBN, when administered prophylactically, may have an effect on angiogenesis . Conversely, rats post-tumor treated with a PBN-derivative, OKN-007, were found to have significantly decreased tumor volumes (~3-fold, p<0.05), decreased the apparent diffusion coefficients (ADC) (~20%, p<0.05), and increased tissue perfusion rates (~60%, p<0.05) in tumors, compared to non-treated rats (Garteiser et al, 2010). OKN-007 was administered in the drinking water at 10 mg/kg/day starting when tumors had reached ~50 mm 3 in volume (about day 15 following intracerebral implantation of rat C6 glioma cells), and continued for a total of 10 days (Garteiser et al, 2010).…”

“…Conversely, rats post-tumor treated with a PBN-derivative, OKN-007, were found to have significantly decreased tumor volumes (~3-fold, p<0.05), decreased the apparent diffusion coefficients (ADC) (~20%, p<0.05), and increased tissue perfusion rates (~60%, p<0.05) in tumors, compared to non-treated rats (Garteiser et al, 2010). OKN-007 was administered in the drinking water at 10 mg/kg/day starting when tumors had reached ~50 mm 3 in volume (about day 15 following intracerebral implantation of rat C6 glioma cells), and continued for a total of 10 days (Garteiser et al, 2010). One group of rats was euthanized after the 10 day treatment period, and a second group was monitored for an additional 25 days following the treatment period (Garteiser et al, 2010).…”

“…From the multiple image slices through a tumor, tumor volumes can be measured, and the growth rate can be calculated from multiple imaging sessions over several days, weeks or months (as shown in Figure 2). Tumor areas are traced in multiple slices to calculate tumor volumes, which can be used to determine tumor growth and doubling times Garteiser et al, 2010). Robust tumor volume determinations can be made by using manual or automated segmentation techniques, which can be used to delineate tumor margins on the basis of signal intensity differences from surrounding brain tissue (Waldman et al, 2009).…”

“…Figure 5 shows an example of an ADC (Fig. 5 b) map in a C6 glioma-bearing rat brain, indicating higher ADC values in tumor tissue compared to contralateral 'normal' brain tissue (Garteiser et al, 2010). Temporal diffusion spectroscopy based on oscillating gradient spin-echo (OGSE) MRI was used to detect microscopic structural variations at the subcellular scale in C6 rat gliomas ( Colvin et al, 2008).…”

“…OKN-007 was administered in the drinking water at 10 mg/kg/day starting when tumors had reached ~50 mm 3 in volume (about day 15 following intracerebral implantation of rat C6 glioma cells), and continued for a total of 10 days (Garteiser et al, 2010). One group of rats was euthanized after the 10 day treatment period, and a second group was monitored for an additional 25 days following the treatment period (Garteiser et al, 2010). In the cohort of animals that were treated for 10 days and then euthanized, percent survival was 100% (p<0.0001), whereas for the rats that were monitored for an additional 25 days the percent survival was greater than 80% (p<0.001) (Garteiser et al, 2010).…”