Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo
Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo
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DOI：
10.1038/sj.gt.3301956
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发表时间：
2003-07-01
期刊：
影响因子：
5.1
通讯作者：
Puri, RK
中科院分区：
文献类型：
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作者：
Kawakami, K;Kawakami, M;Puri, RK
白细胞介素-13受体(IL-13R) α 2链在配体结合和内化中起关键作用。我们最近证明了这种细胞因子受体链在肿瘤生物学中具有独特的特征：它在动物模型中抑制乳腺癌和胰腺癌的致瘤性。在本研究中，我们利用IL-13Ralpha2链，建立了胰腺癌治疗的新途径。为此，将编码IL-13Ralpha2链基因的质粒与脂质体混合，注射到免疫缺陷小鼠皮下或原位异种移植的人胰腺肿瘤中，然后用重组IL-13细胞毒素进行全身或局部治疗。只有被迫表达IL-13Ralpha2链的肿瘤才对IL-13细胞毒素的抗肿瘤作用极度敏感。退行性肿瘤以巨噬细胞和自然杀伤细胞为主浸润。由于发现巨噬细胞产生一氧化氮，il - 13ralpha2靶向癌症治疗不仅涉及IL-13细胞毒素直接杀死肿瘤细胞，还涉及肿瘤部位先天免疫反应的激活。因此，这种方法可能成为胰腺癌或其他局部癌症治疗的一种新的有力工具。
Interleukin-13 receptor (IL-13R) alpha2 chain plays a key role in ligand binding and internalization. We have recently demonstrated that this cytokine receptor chain has unique characteristics in tumor biology: it inhibits tumorigenicity of breast and pancreatic cancer in animal models. In this study, we have exploited IL-13Ralpha2 chain and established a novel approach for pancreatic cancer therapy. For this, a plasmid encoding the IL-13Ralpha2 chain gene was mixed with liposomes and injected into subcutaneously or orthotopically xenografted human pancreatic tumors in immunodeficient mice, followed by systemic or local therapy by a recombinant IL-13 cytotoxin. Only tumors forced to express IL-13Ralpha2 chain acquired extreme susceptibility to the antitumor effect of IL-13 cytotoxin. There was a dominant infiltration of cells including macrophages and natural killer cells in the regressing tumors. Since macrophages were found to produce nitric oxide, IL-13Ralpha2-targeted cancer therapy involved not only a direct tumor cell killing by IL-13 cytotoxin but also activation of innate immune response at the tumor site. Therefore, this approach may be a new powerful tool for pancreatic cancer or other localized cancer therapy.