A Caspase-6 and Anti-HER2 Antibody Chimeric Tumor-Targeted Proapoptotic Molecule Decreased Metastasis of Human Osteosarcoma
A Caspase-6 and Anti-HER2 Antibody Chimeric Tumor-Targeted Proapoptotic Molecule Decreased Metastasis of Human Osteosarcoma
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Caspase-6 和抗 HER2 抗体嵌合肿瘤靶向促凋亡分子减少人骨肉瘤的转移
DOI：
10.1080/07357900802427935
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发表时间：
2009-01-01
影响因子：
2.4
通讯作者：
Yang, An-Gang
中科院分区：
文献类型：
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作者：
Wang, Li-Feng;Zhou, Yong;Yang, An-Gang
在20-40%的乳腺癌、卵巢癌、子宫内膜癌、胃癌、膀胱癌、前列腺癌或肺癌患者中检测到由于基因扩增而过表达的人生长因子受体-2（HER 2），其与许多肿瘤的转移相关，并且被认为是这些肿瘤的不良预后指标。然而，该数据对于HER 2过表达和骨肉瘤的预后是有争议的，骨肉瘤是最常见的原发性恶性骨肿瘤，由于其转移和对当前治疗的不良反应，在医学肿瘤学中提出了治疗挑战。我们以前报道过，由HER 2特异性单链抗体与假单胞菌外毒素A（PEA）的结构域II和截短的活性caspase-6的5'端融合的immunocasp-6基因可以选择性地抑制HER 2阳性肿瘤的生长。在这项研究中，我们扩展了它的应用。我们首先证实了转移性骨肉瘤SOSP-9607（E10）细胞表面的HER 2高表达，然后在体外证明了其特异性地依赖于免疫卡蛋白-6诱导的细胞杀伤。此后，在骨肉瘤肺转移小鼠模型中使用肌内（i.m.）注射脂质体包封的载体。我们的结果表明，immunocasp-6基因的表达不仅显着延长动物的生存，而且大大抑制肿瘤转移。因此，我们的策略提出了一种治疗HER 2/neu阳性骨肉瘤的替代方法。
Human growth factor receptor-2 (HER2), overexpressed as a result of gene amplification, is detected in 20-40% of patients with breast, ovarian, endometrial, gastric, bladder, prostate, or lung cancers, correlated to metastasis of many tumors, and considered to be a poor prognostic indicator for these tumors. However, the data was controversial for HER2 overexpression and the prognosis of osteosarcoma, which is the most common primary malignant bone tumor, presents a therapeutic challenge in medical oncology due to its metastasis and poor response to current treatments. Previously, we reported that the immunocasp-6 gene fused by a HER2-specific single-chain antibody with domain II of Pseudomonas exotoxin A (PEA) and the 5' end of the truncated active caspase-6 could selectively suppress the HER2-positive tumor growth. In this study, we extend its application. We first confirmed the higher HER2 expression on the surface of metastatic osteosarcoma SOSP-9607(E10) cells, which then be proved specifically addicted to immunocasp-6-induced cells killing in vitro. Thereafter, the efficacy of immunocasp-6 was tested in an osteosarcoma lung metastasis mouse model using intramuscular (i.m.) injections of liposome-encapsulated vectors. Our results showed that the expression of the immunocasp-6 gene not only significantly prolonged animal's survival, but also greatly inhibited tumor metastasis. Thereby, our strategy suggests an alternative approach to treating HER2/neu-positive osteosarcoma.