期刊
NEURO-ONCOLOGY
卷 15, 期 3, 页码 330-340出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/nos337
关键词
anti-glioma therapy; bioluminescence imaging; F98 rat glioma model; in vivo; magnetic resonance imaging; nitrone OKN-007; U87 xenografts
资金
- Oklahoma Medical Research Foundation
- Oklahoma Center for the Advancement of Science and Technology [AR092-049]
- Huntsman Cancer Center from the National Cancer Institute [P30CA042014]
Background. Glioblastoma multiforme, a World Health Organization grade IV glioma, has a poor prognosis in humans despite current treatment options. Here, we present magnetic resonance imaging (MRI) data regarding the regression of aggressive rat F98 gliomas and human U87 glioma xenografts after treatment with the nitrone compound OKN-007, a disulfonyl derivative of alpha-phenyl-tert-butyl nitrone. Methods. MRI was used to assess tumor volumes in F98 and U87 gliomas, and bioluminescence imaging was used to measure tumor volumes in F98 gliomas encoded with the luciferase gene (F98(luc)). Immunohistochemistry was used to assess angiogenesis (vascular endothelial growth factor [VEGF] and microvessel density [MVD]), cell differentiation (carbonic anhydrase IX [CA-IX]), hypoxia (hypoxia-inducible factor-1 alpha [HIF-1 alpha], cell proliferation (glucose transporter 1 [Glut-1] and MIB-1), proliferation index, and apoptosis (cleaved caspase 3) markers in F98 gliomas. VEGF, CA-IX, Glut-1, HIF-1 alpha, and cleaved caspase 3 were assessed in U87 gliomas. Results. Animal survival was found to be significantly increased (P < .001 for F98, P < .01 for U87) in the group that received OKN-007 treatment compared with the untreated groups. After MRI detection of F98 gliomas, OKN-007, administered orally, was found to decrease tumor growth (P < .05). U87 glioma volumes were found to significantly decrease (P < .05) after OKN-007 treatment, compared with untreated animals. OKN-007 administration resulted in significant decreases in tumor hypoxia (HIF-1 alpha [P < .05] in both F98 and U87), angiogenesis (MVD [P < .05], but not VEGF, in F98 or U87), and cell proliferation (Glut-1 [P < .05 in F98, P < .01 in U87] and MIB-1 [P < .01] in F98) and caused a significant increase in apoptosis (cleaved caspase 3 [P < .001 in F98, P < .05 in U87]), compared with untreated animals. Conclusions. OKN-007 may be considered as a promising therapeutic addition or alternative for the treatment of aggressive human gliomas.
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