Kawakami Koji, Kawakami Mariko, Liu Qi, Puri Raj K
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):230-7. doi: 10.1016/j.ijrobp.2005.05.017.
Interleukin-13 receptor-targeted cytotoxin (IL13-PE38) is highly cytotoxic to human glioblastoma (GBM) cells. Although this molecule is being tested in a multicenter Phase III clinical trial (PRECISE Study) in patients with recurrent disease, the activity of IL13-PE38 when combined with radiation therapy has not been investigated.
Cytotoxicity of IL13-PE38 to GBM cell lines was assessed by protein synthesis inhibition and clonogenic assays, and the growth of GBM cells receiving radiation was assessed by thymidine uptake assays. Expression of IL-13 receptor alpha2 (IL-13Ralpha2) messenger ribonucleic acid (mRNA) in GBM cells exposed to radiation was assessed by quantitative reverse transcriptase/polymerase chain reaction (RT-PCR) and IL-13R density by radiolabeled IL-13 binding assays.
Prior irradiation of GBM cell lines followed by IL13-PE38 treatment did not enhance cytotoxicity; however, concomitant 5 Gy irradiation and IL13-PE38 treatment was highly cytotoxic to T98G, M059K, A172, and LN-229 cell lines as determined by cell viability assays. There was a statistically significant decrease in number of viable cells in IL13-PE38 and irradiated cells compared with irradiated cells alone (p < 0.05) or IL13-PE38 treated cells alone (p < 0.05). In contrast, U251, SN19, and U87MG cell lines did not show any combined effect. These results were confirmed by clonogenic assays. Although three GBM cell lines-U251, SN19, and A172-showed 2.8- to 13.9-fold upregulation of IL-13Ralpha2 mRNA expression at 6-24 h after exposure to 5 Gy radiation, specific binding of radiolabeled IL-13 to these cell lines did not improve.
Our results suggest that concomitant radiation therapy and IL13-PE38 treatment may be beneficial for the treatment of patients with GBM. This strategy may be worth exploring in animal models of human glioma.
白细胞介素-13受体靶向细胞毒素（IL13-PE38）对人胶质母细胞瘤（GBM）细胞具有高度细胞毒性。尽管该分子正在复发疾病患者的多中心III期临床试验（PRECISE研究）中进行测试，但尚未研究IL13-PE38与放射治疗联合使用时的活性。
通过蛋白质合成抑制和克隆形成试验评估IL13-PE38对GBM细胞系的细胞毒性，通过胸苷摄取试验评估接受放射治疗的GBM细胞的生长。通过定量逆转录酶/聚合酶链反应（RT-PCR）评估暴露于放射治疗的GBM细胞中白细胞介素-13受体α2（IL-13Rα2）信使核糖核酸（mRNA）的表达，并通过放射性标记的IL-13结合试验评估IL-13R密度。
GBM细胞系先进行放射治疗然后进行IL13-PE38治疗并没有增强细胞毒性；然而，通过细胞活力试验确定，5 Gy放射治疗与IL13-PE38联合治疗对T98G、M059K、A172和LN-229细胞系具有高度细胞毒性。与单独接受放射治疗的细胞（p < 0.05）或单独接受IL13-PE38治疗的细胞（p < 0.05）相比，IL13-PE38与放射治疗的细胞中活细胞数量有统计学显著减少。相比之下，U251、SN19和U87MG细胞系未显示任何联合效应。这些结果通过克隆形成试验得到证实。尽管三个GBM细胞系——U251、SN19和A172——在暴露于5 Gy放射治疗后6至24小时显示IL-13Rα2 mRNA表达上调2.8至13.9倍，但放射性标记的IL-13与这些细胞系的特异性结合并未改善。
我们的结果表明，放射治疗与IL13-PE38联合治疗可能对GBM患者的治疗有益。该策略可能值得在人胶质瘤动物模型中进行探索。
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