OKN-007 decreases tumor necrosis and tumor cell proliferation and increases apoptosis in a preclinical F98 rat glioma model.
BACKGROUND
Glioblastoma is a malignant World Health Organization (WHO) grade IV glioma with a poor prognosis in humans. New therapeutics are desperately required. The nitrone OKN-007 (2,4-disulfophenyl-PBN) has demonstrated effective anti-glioma properties in several rodent models and is currently being used as a clinical investigational drug for recurrent gliomas. We assessed the regional effects of OKN-007 in the tumor necrotic core and non-necrotic tumor parenchyma.


METHODS
An F98 rat glioma model was evaluated using proton magnetic resonance spectroscopy ((1) H-MRS), diffusion-weighted imaging (DWI), morphological T2-weighted imaging (T2W) at 7 Tesla (30 cm-bore MRI), as well as immunohistochemistry and microarray assessments, at maximum tumor volumes (15-23 days following cell implantation in untreated (UT) tumors, and 18-35 days in OKN-007-treated tumors).


RESULTS
(1) H-MRS data indicates that Lip0.9/Cho, Lip0.9/Cr, Lip1.3/Cho, and Lip1.3/Cr ratios are significantly decreased (all P < 0.05) in the OKN-007-treated group compared with UT F98 gliomas. The Cho/Cr ratio is also significantly decreased in the OKN-007-treated group compared with UT gliomas. In addition, the OKN-007-treated group demonstrates significantly lower ADC values in the necrotic tumor core and the nonnecrotic tumor parenchyma (both P < 0.05) compared with the UT group. There was also an increase in apoptosis following OKN-007 treatment (P < 0.01) compared with UT.


CONCLUSIONS
OKN-007 reduces both necrosis and tumor cell proliferation, as well as seems to mediate multiple effects in different tumor regions (tumor necrotic core and nonnecrotic tumor parenchyma) in F98 gliomas, indicating the efficacy of OKN-007 as an anti-cancer agent and its potential clinical use.
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.|Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma, USA.
Patricia Coutinho
PC
de Souza
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Krithika
K
Balasubramanian
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Charity
C
Njoku
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Natalyia
N
Smith
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
David L
DL
Gillespie
Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah, USA.
Andrea
A
Schwager
Department of Bioengineering, University of Utah, Salt Lake City, Utah, USA.
Osama
O
Abdullah
Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma, USA.
Jerry W
JW
Ritchey
Department of Pathology, Oklahoma University Health Science Center, Oklahoma City, Oklahoma, USA.
Kar-Ming
KM
Fung
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Debra
D
Saunders
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.|Departments of Neurosurgery, Radiation Oncology, Oncological Sciences, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.
Randy L
RL
Jensen
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.|Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma, USA.|Department of Pathology, Oklahoma University Health Science Center, Oklahoma City, Oklahoma, USA.
Rheal A
RA
Towner
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007097:Imines / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009336:Necrosis / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007097:Imines; C552724:OKN 007
OKN-007; diffusion-weighted imaging; glioma; necrosis; proton magnetic resonance spectroscopy