Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
J Neurosurg. 2011 Oct;115(4):749-53. doi: 10.3171/2011.5.JNS101954. Epub 2011 Jun 17.
Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor.
The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor-1α (HIF-1α) protein expression were measured 1 day afterward.
On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203-6836), and that of the contralateral brain tissue was 1017 (range 488-2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 ± 0.063 and 0.69 ± 0.062, respectively (mean ± SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1α and CA9 in all tumor specimens.
Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment.
据信高级别神经胶质瘤存在肿瘤内缺氧。反式钠 crocetinate（TSC）已被证明可增加缺氧组织的氧气扩散。在这项研究中，作者使用氧敏感 PET 研究来评估胶质母细胞瘤模型中体内缺氧的程度以及 TSC 对肿瘤基线氧合作用的影响。
C6 神经胶质瘤细胞立体定向植入大鼠大脑右侧额区。通过磁共振成像确认颅内肿瘤的形成。将铜（II）乙酰二（N4-甲基硫代半卡巴腙）（Cu-ATSM）注射到动物体内，然后分别给予 TSC 或生理盐水（每组 6 只）。进行正电子发射断层扫描成像，并计算相对摄取值以确定肿瘤和正常脑组织内的氧合作用。此外，向动物输注 TSC 或生理盐水，并在 1 天后测量碳酸酐酶 9（CA9）和缺氧诱导因子-1α（HIF-1α）的蛋白表达。
在 PET 成像上，所有胶质母细胞瘤肿瘤与对侧大脑半球相比，Cu-ATSM 的摄取均有统计学意义上的降低（p = 0.000002）。肿瘤的平均相对摄取值为 3900（范围 2203-6836），对侧脑组织的摄取值为 1017（范围 488-2304）。生理盐水组和 TSC 组（每组 6 只）的平均相对缺氧肿瘤体积分别为 1.01±0.063 和 0.69±0.062（平均值±SEM，p = 0.002）。TSC 输注导致缺氧体积减少 31%。免疫印迹分析显示所有肿瘤标本中均表达 HIF-1α 和 CA9。
一些胶质母细胞瘤表现出可通过氧特异性 PET 成像检测到的缺氧。TSC 似乎可在功能成像上减轻肿瘤内缺氧。进一步的研究应探讨胶质母细胞瘤的相对缺氧以及在辅助治疗期间减轻缺氧可能带来的潜在治疗收益。
