Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models.
Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models.
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我们用MRS研究了胆碱激酶抑制剂JAS239对胶质母细胞瘤(GBM)代谢的影响。除了抑制磷酸胆碱合成外，我们还研究了与GBM进展和治疗反应相关的其他关键代谢通路的变化。采用3种同基因大鼠模型：F98(N = 12)和9L(N = 8)模型和GL2 61(N = 10)模型。将大鼠右侧大脑皮质内注射GBM细胞，用T2加权图像监测肿瘤生长情况。分别以4 mg/kgJAS239(F98大鼠，n = 6；9L大鼠，n = 6；GL261小鼠，n = 5)或生理盐水(对照组，F98大鼠，n = 6；9L大鼠，n = 2；GL261小鼠，n = 5)腹腔注射，每日1次，连续5d。在第0天(T0，基线)和第6天(T6，治疗结束)，使用PRESS序列从肿瘤和对侧正常脑获取单体素频谱。代谢产物比率(Tcho/Tcr、Tcho/NAA、mi/Tcr、Glx/Tcr和(Lip + Lac)/Cr)的变化被用来评估对JAS239的反应的代谢途径的改变。与生理盐水处理的动物相比，所有模型的肿瘤生长受阻，F98模型的肿瘤生长明显减少(p <； 0.05)。在所有的GBM模型中，JAS239治疗后Tcho/TCR均下降，表明磷脂代谢降低，其中9L下降最大，其次是GL261和F98肿瘤。在9L模型中，Tcho/NAA值显著降低(p <； 0.05)。与生理盐水组相比，JAS239处理的F98肿瘤的mI/Tcr显著降低(p <； 0.05)。仅在F98和9L肿瘤中观察到GLX/TCR下降的趋势不明显。JAS239处理的F98肿瘤细胞也显示Lip + Lac显著增加(p <； 0.05)，表明细胞死亡增加。这项研究证明了磁共振波谱在评估胆碱激酶抑制反应中基底膜的代谢变化中的作用。应用磁共振波谱技术研究了胆碱激酶抑制剂JAS239对3种同基因鼠脑胶质母细胞瘤(GBM)代谢的影响。与生理盐水处理的动物相比，JAS239治疗对所有模型的肿瘤生长都有抑制作用。在9L模型中，Tcho/nAa比值显著降低；在F98肿瘤中，mI/Tcr显著降低，而Lip + Lac显著升高，表明细胞死亡增加。
Changes in glioblastoma (GBM) metabolism was investigated in response to JAS239, a choline kinase inhibitor, using MRS. In addition to the inhibition of phosphocholine synthesis, we investigated changes in other key metabolic pathways associated with GBM progression and treatment response. Three syngeneic rodent models of GBM were used: F98 (N = 12) and 9L (N = 8) models in rats and GL261 (N = 10) in mice. Rodents were intracranially injected with GBM cells in the right cortex and tumor growth was monitored using T 2‐weighted images. Animals were treated once daily with intraperitoneal injections of 4 mg/kg JAS239 (F98 rats, n = 6; 9L rats, n = 6; GL261 mice, n = 5) or saline (control group, F98 rats, n = 6; 9L rats, n = 2; GL261 mice, n = 5) for five consecutive days. Single voxel spectra were acquired on Days 0 (T0, baseline) and 6 (T6, end of treatment) from the tumor as well as the contralateral normal brain using a PRESS sequence. Changes in metabolite ratios (tCho/tCr, tCho/NAA, mI/tCr, Glx/tCr and (Lip + Lac)/Cr) were used to assess metabolic pathway alterations in response to JAS239. Tumor growth arrest was noted in all models in response to JAS239 treatment compared with saline‐treated animals, with a significant reduction (p < 0.05) in the F98 model. A reduction in tCho/tCr was observed with JAS239 treatment in all GBM models, indicating reduced phospholipid metabolism, with the highest reduction in 9L followed by GL261 and F98 tumors. A significant reduction (p < 0.05) in the tCho/NAA ratio was observed in the 9L model. A significant reduction in mI/tCr (p < 0.05) was found in JAS239‐treated F98 tumors compared with the saline‐treated animals. A non‐significant trend of reduction in Glx/tCr was observed only in F98 and 9L tumors. JAS239‐treated F98 tumors also showed a significant increase in Lip + Lac (p < 0.05), indicating increased cell death. This study demonstrated the utility of MRS in assessing metabolic changes in GBM in response to choline kinase inhibition. Changes in glioblastoma (GBM) metabolism were investigated in response to JAS239, a choline kinase inhibitor, using MRS in three syngeneic rodent models of GBM. Tumor growth arrest was noted in all models in response to JAS239 treatment compared with saline‐treated animals. A significant reduction in the tCho/NAA ratio was observed with treatment in the 9L model; a significant reduction in mI/tCr was found with treatment in F98 tumors along with significant increase in Lip + Lac with treatment, indicating increased cell death.
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影响因子：
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作者：
Arlauckas SP;Kumar M;Popov AV;Poptani H;Delikatny EJ
通讯作者：
Delikatny EJ
影响因子：
12.4
作者：
Caniglia JL;Jalasutram A;Asuthkar S;Sahagun J;Park S;Ravindra A;Tsung AJ;Guda MR;Velpula KK
通讯作者：
Velpula KK
影响因子：
3.8
作者：
Chung FY;Huang MY;Yeh CS;Chang HJ;Cheng TL;Yen LC;Wang JY;Lin SR
通讯作者：
Lin SR
DOI：
10.1038/nrc3162
发表时间：
2011-11-17
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
18.4
作者：
Hambardzumyan D;Bergers G
通讯作者：
Bergers G