Nitrone OKN-007 抑制 F98 和 U87 大鼠脑胶质瘤模型肿瘤生长的作用
Regression of glioma tumor growth in F98 and U87 rat glioma models by the Nitrone OKN-007.
机构信息
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.
出版信息
Neuro Oncol. 2013 Mar;15(3):330-40. doi: 10.1093/neuonc/nos337. Epub 2013 Jan 17.
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 α-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-1α [HIF-1α]), 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-1α, 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-1α [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.
背景
胶质母细胞瘤多形性，一种世界卫生组织四级神经胶质瘤，尽管目前有治疗选择，但人类预后较差。在这里，我们提供磁共振成像（MRI）数据，显示硝基化合物 OKN-007 治疗后侵袭性大鼠 F98 神经胶质瘤和人 U87 神经胶质瘤异种移植物的消退，OKN-007 是 α-苯基-叔丁基氮氧自由基的二磺酰衍生物。
方法
MRI 用于评估 F98 和 U87 神经胶质瘤的肿瘤体积，生物发光成像用于测量编码荧光素酶基因的 F98 神经胶质瘤的肿瘤体积（F98（luc））。免疫组织化学用于评估血管生成（血管内皮生长因子[VEGF]和微血管密度[MVD]）、细胞分化（碳酸酐酶 IX[CA-IX]）、缺氧（缺氧诱导因子-1α[HIF-1α]）、细胞增殖（葡萄糖转运蛋白 1[Glut-1]和 MIB-1）、增殖指数和凋亡（cleaved caspase 3）标志物在 F98 神经胶质瘤中的表达。评估 U87 神经胶质瘤中的 VEGF、CA-IX、Glut-1、HIF-1α 和 cleaved caspase 3。
结果
与未治疗组相比，接受 OKN-007 治疗的动物的存活率明显增加（F98 为 P <.001，U87 为 P <.01）。在 F98 神经胶质瘤的 MRI 检测后，发现 OKN-007 经口给药可抑制肿瘤生长（P <.05）。与未治疗动物相比，U87 神经胶质瘤体积明显减小（P <.05）。OKN-007 给药导致肿瘤缺氧显著降低（HIF-1α[P <.05]，F98 和 U87 均有）、血管生成（MVD[P <.05]，但 F98 或 U87 无 VEGF）和细胞增殖（Glut-1[F98 中 P <.05，U87 中 P <.01]和 MIB-1[F98 中 P <.01]），并导致凋亡显著增加（cleaved caspase 3[F98 中 P <.001，U87 中 P <.05]），与未治疗动物相比。
结论
OKN-007 可被认为是治疗侵袭性人类神经胶质瘤的一种有前途的治疗方法。
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