Interleukin-4 cytotoxin therapy synergizes with gemcitabine in a mouse model of pancreatic ductal adenocarcinoma
Interleukin-4 cytotoxin therapy synergizes with gemcitabine in a mouse model of pancreatic ductal adenocarcinoma
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DOI：
10.1158/0008-5472.can-06-4558
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Puri, Raj K.
中科院分区：
文献类型：
--
作者：
Shimamura, Takeshi;Royal, Richard E.;Puri, Raj K.
利用细胞毒素或免疫毒素靶向细胞表面受体为肿瘤治疗提供了独特的机会。在此，我们在胰腺导管腺癌（PDA）动物模型中展示了吉西他滨与一种由白细胞介素 - 4（IL - 4）和截短的铜绿假单胞菌外毒素组成的IL - 4细胞毒素联合治疗的疗效。我们观察到，70例PDA患者的肿瘤样本中有42例（60%）表达中到高密度的表面IL - 4受体（11,411），而正常胰腺样本不表达或表达低密度的IL - 4受体。IL - 4细胞毒素对8种胰腺癌细胞系中的6种具有特异性且高度的细胞毒性[50%蛋白质合成抑制（IC50）范围从>0.1到13 ng/mL]，而在正常人胰腺导管上皮细胞、成纤维细胞和人脐静脉内皮细胞（HUVEC）中未观察到细胞毒性（IC50>1000 ng/mL）。我们还表明，IL - 4细胞毒素与吉西他滨联合在体外表现出协同的抗肿瘤活性。为了在体内确认协同的抗肿瘤活性并监测精确的实时疾病进展，我们使用了一种新型的转移和原位小鼠模型，该模型使用绿色荧光蛋白转染的癌细胞和全身成像系统。两种药物联合使用使40%患有已形成的小型PDA肿瘤的裸鼠的肿瘤完全根除。此外，联合治疗显著延长了携带第14天晚期远处转移性PDA肿瘤的裸鼠的生存期。在移植了来自一名接受手术切除的患者的PDA的小鼠中也观察到了类似的结果。这些结果表明，IL - 4细胞毒素与吉西他滨联合可能为PDA患者的治疗提供有效的疗法。
Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for tumor therapy. Here, we show the efficacy of the combination therapy of gemcitabine with an interleukin-4 (IL-4) cytotoxin composed of IL-4 and truncated Pseudomonas exotoxin in animal models of pancreatic ductal adenocarcinoma (PDA). We have observed that 42 of 70 (60%) tumor samples from patients with PDA express moderate- to high-density surface IL-4 receptor (11,411), whereas normal pancreatic samples express no or low-density IL-4R. IL-4 cytotoxin was specifically and highly cytotoxic [50% protein synthesis inhibition (IC50) ranging from >0.1 to 13 ng/mL] to six of eight pancreatic cancer cell lines, whereas no cytotoxicity (IC50 >1,000 ng/mL) was observed in normal human pancreatic duct epithelium cells, fibroblasts, and human umbilical vein endothelial cells (HUVEC). We also showed that IL-4 cytotoxin in combination with gemcitabine exhibited synergistic antitumor activity in vitro. To confirm synergistic antitumor activity in vivo and monitor precise real-time disease progression, we used a novel metastatic and orthotopic mouse model using green fluorescent protein-transfected cancer cells and whole-body imaging system. The combination of both agents caused complete eradication of tumors in 40% of nude mice with small established PDA tumors. In addition, combined treatment significantly prolonged the survival of nude mice bearing day 14 advanced distant metastatic PDA tumors. Similar results were observed in mice xenografted with PDA obtained from a patient undergoing surgical resection. These results indicate that IL-4 cytotoxin combined with gemcitabine may provide effective therapy for the treatment of patients with PDA.