Kioi Mitomu, Shimamura Takeshi, Nakashima Hideyuki, Hirota Makoto, Tohnai Iwai, Husain Syed R, Puri Raj K
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Int J Cancer. 2009 Mar 15;124(6):1440-8. doi: 10.1002/ijc.24067.
Interleukin-13 receptor-targeted cytotoxin (IL13-PE38) is highly cytotoxic to certain types of human cancers expressing abundant levels of IL-13Ralpha2 chain. Although IL13-PE38 is being tested in a Phase III clinical trial in brain tumors, the activity of IL13-PE38 alone or when combined with taxane, a chemotherapeutic drug for oral squamous cell carcinoma (OSCC), has not been investigated. Here, we show that approximately 40% of OSCCs (n = 50) in a tissue array are strongly positive for IL-13Ralpha2, whereas normal oral mucosa (n = 10) expresses very low or undetectable levels evaluated by immunohistochemistry. IL13-PE38 was highly cytotoxic to OSCC cell lines, but not cytotoxic to normal oral fibroblasts. IL13-PE38 mediated a synergistic antitumor effect with paclitaxel in OSC-19 in vitro and in vivo in the orthotopic OSCC tongue tumor model. Real-time tumor growth was monitored by optical imaging using a Xenogen-IVIS imaging system. Treated animals showed significant (p < 0.05) improvement in survival, which correlated with in vivo imaging of tumor response without evidence of visible toxicity. Gene transfer of IL-13Ralpha2 in oral cancer cells increased sensitivity of OSCC cell line to IL13-PE38 in vitro. Retrovirus-mediated gene-transfer of IL-13Ralpha2 in HSC-3 into tongue tumors in vivo dramatically enhanced the antitumor activity of IL13-PE38, providing complete elimination of established tumors and prolonging survival of these animals. These results indicate that IL13-PE38 in combination with paclitaxel acting via different mechanisms may be a potential treatment option for IL-13Ralpha2 expressing OSCC or for the treatment of non-IL-13Ralpha2 expressing OSCC combined with gene transfer of IL-13Ralpha2.
白细胞介素-13受体靶向细胞毒素（IL13-PE38）对某些表达高水平白细胞介素-13受体α2链的人类癌症具有高度细胞毒性。尽管IL13-PE38正在脑肿瘤的III期临床试验中进行测试，但尚未研究IL13-PE38单独使用或与紫杉烷（一种用于口腔鳞状细胞癌（OSCC）的化疗药物）联合使用时的活性。在这里，我们表明，在组织芯片中，约40%的OSCC（n = 50）对IL-13Rα2呈强阳性，而通过免疫组织化学评估，正常口腔黏膜（n = 10）表达的水平非常低或无法检测到。IL13-PE38对OSCC细胞系具有高度细胞毒性，但对正常口腔成纤维细胞无细胞毒性。在原位OSCC舌肿瘤模型中，IL13-PE38在体外和体内与紫杉醇在OSC-19中介导了协同抗肿瘤作用。使用Xenogen-IVIS成像系统通过光学成像监测实时肿瘤生长。治疗的动物在生存方面有显著改善（p < 0.05），这与肿瘤反应的体内成像相关，且没有明显毒性的证据。口腔癌细胞中IL-13Rα2的基因转移增加了OSCC细胞系在体外对IL13-PE38的敏感性。逆转录病毒介导的IL-13Rα2基因转移到体内的HSC-3舌肿瘤中显著增强了IL13-PE38的抗肿瘤活性，实现了对已建立肿瘤的完全消除并延长了这些动物的生存期。这些结果表明，IL13-PE38与通过不同机制起作用的紫杉醇联合使用，可能是表达IL-13Rα2的OSCC的潜在治疗选择，或用于治疗不表达IL-13Rα2的OSCC并联合IL-13Rα2基因转移。
