Husain S R, Behari N, Kreitman R J, Pastan I, Puri R K
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Cancer Res. 1998 Aug 15;58(16):3649-53.
No curative therapy is available for malignant gliomas. We have discovered that human glioblastoma cells express high affinity interleukin-4 receptor (IL-4R), which is an attractive target for receptor-directed IL-4 toxin therapy. The IL-4 toxin, IL-4(38-37)-PE38KDEL, is a fusion protein containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4. The IL-4 toxin binds specifically to the IL-4R and is highly cytotoxic to glioblastoma cells, as determined by clonogenic and protein synthesis inhibition assays. Intratumoral administration of the IL-4 toxin given on alternate days for 3-4 doses into U251 glioblastoma flank tumors in nude mice, showed a complete remission of small (approximately 13 mm3) and large (approximately 60 mm3) tumors in all animals, without any evidence of toxicity. A significant antitumor activity was also observed when the IL-4 toxin was administered via i.p. and i.v. routes. These results demonstrate that the IL-4 toxin may be a new therapeutic drug for the treatment of human glioblastoma. Therefore, we have begun a Phase I clinical trial with IL-4(38-37)-PE38KDEL for treatment of human glioblastoma.
目前尚无针对恶性胶质瘤的治愈性疗法。我们发现人类胶质母细胞瘤细胞表达高亲和力白细胞介素-4受体（IL-4R），这是受体导向性IL-4毒素疗法的一个有吸引力的靶点。IL-4毒素IL-4(38-37)-PE38KDEL是一种融合蛋白，包含铜绿假单胞菌外毒素的转位和酶结构域以及环化排列的人IL-4。通过克隆形成和蛋白质合成抑制试验确定，IL-4毒素特异性结合IL-4R，对胶质母细胞瘤细胞具有高度细胞毒性。在裸鼠U251胶质母细胞瘤侧腹肿瘤中每隔一天瘤内注射IL-4毒素，共注射3-4剂，结果显示所有动物的小肿瘤（约13立方毫米）和大肿瘤（约60立方毫米）均完全缓解，且无任何毒性迹象。当通过腹腔注射和静脉注射途径给予IL-4毒素时，也观察到了显著的抗肿瘤活性。这些结果表明，IL-4毒素可能是一种治疗人类胶质母细胞瘤的新型治疗药物。因此，我们已经开始了一项使用IL-4(38-37)-PE38KDEL治疗人类胶质母细胞瘤的I期临床试验。
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