Kiwit J C, Schmitz K H, Daum L, Reifenberger G, Roosen N
Neurosurgical Clinic, Heinrich-Heine-University Medical School, Düsseldorf, Germany.
J Neurosurg. 1991 Oct;75(4):597-603. doi: 10.3171/jns.1991.75.4.0597.
In a study examining the possible therapeutic effects of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) on malignant gliomas without expression of tumor necrosis factor (TNF)-receptors, RG-2 glioma cells were tested in vitro as well as in a rat experimental glioma model. A growth inhibition assay revealed no inhibiting effect in vitro up to a concentration of 20 micrograms/ml rHuTNF-alpha. Receptor-binding studies showed that RG-2 cells did not present specific receptors for rHuTNF-alpha. The pharmacokinetics of rHuTNF-alpha after intravenous injection were studied with respect to serum, tissue, and brain tumor concentrations and showed increased glioma concentrations of (mean +/- standard error of the mean) 0.47 +/- 0.18 ng TNF/mg brain compared to 0.15 +/- 0.05 ng TNF/mg brain in the normal contralateral hemisphere. No therapeutic effect on solid RG-2 gliomas could be observed after stereotactic injection of 7.3 micrograms rHuTNF/10 microliter buffer solution into the tumor in 10 animals. Immunohistochemical studies after stereotactic injection of rHuTNF-alpha showed total disappearance of the substance after 24 hours without internalization into tumor cells. Stereotactic injection of 7.3 micrograms rHuTNF 10 microliters into normal brain resulted in marked inflammatory response around the injection track, including microvascular thrombosis. These results demonstrate that rHuTNF has neither direct nor indirect cytotoxic activity on RG-2 glioma cells. Furthermore, before clinical use of rHuTNF-alpha in malignant gliomas, the authors suggest that receptor studies be done in each patient. In receptor-positive patients undergoing treatment with rHuTNF-alpha, precautions should be taken to prevent local encephalitic reactions.
在一项研究重组人肿瘤坏死因子-α（rHuTNF-α）对不表达肿瘤坏死因子（TNF）受体的恶性胶质瘤可能的治疗作用中，RG-2胶质瘤细胞在体外以及大鼠实验性胶质瘤模型中进行了测试。生长抑制试验显示，在rHuTNF-α浓度高达20微克/毫升时，体外无抑制作用。受体结合研究表明，RG-2细胞不存在rHuTNF-α的特异性受体。对静脉注射后rHuTNF-α的药代动力学进行了血清、组织和脑肿瘤浓度方面的研究，结果显示，与对侧正常半球中0.15±0.05纳克TNF/毫克脑相比，胶质瘤浓度增加至（平均值±平均标准误差）0.47±0.18纳克TNF/毫克脑。在10只动物的肿瘤中立体定向注射7.3微克rHuTNF/10微升缓冲溶液后，未观察到对实体RG-2胶质瘤有治疗作用。立体定向注射rHuTNF-α后的免疫组织化学研究显示，该物质在24小时后完全消失，未内化进入肿瘤细胞。向正常脑内立体定向注射7.3微克rHuTNF/10微升导致注射轨迹周围出现明显炎症反应，包括微血管血栓形成。这些结果表明，rHuTNF对RG-2胶质瘤细胞既无直接也无间接细胞毒性活性。此外，作者建议在将rHuTNF-α临床用于恶性胶质瘤之前，应对每位患者进行受体研究。在接受rHuTNF-α治疗的受体阳性患者中，应采取预防措施以防止局部脑炎反应。
