Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter
Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter
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DOI：
10.1093/jnci/90.14.1080
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发表时间：
1998-07-15
影响因子：
10.3
通讯作者：
Grandis, JR
中科院分区：
文献类型：
--
作者：
He, YK;Zeng, Q;Grandis, JR
背景资料：与正常粘膜鳞状上皮细胞不同，头颈部鳞状细胞癌（SCCHN）过度表达表皮生长因子受体（EGFR）信使RNA和蛋白，EGFR蛋白是维持SCCHN细胞体外增殖所必需的。为了确定EGFR表达是否有助于肿瘤生长，我研究了通过原位表达反义寡核苷酸来抑制肿瘤异种移植物中EGFR表达的效果。方法：使用瘤内阳离子脂质体介导的基因转移将能够表达有义或反义EGFR序列的质粒递送到人头颈部肿瘤中，这些肿瘤作为裸小鼠皮下异种移植物生长。寡核苷酸在U6 RNA启动子的控制下表达。结果如下：将EGFR反义（而非相应的正义）质粒构建体直接接种到已建立的SCCHN异种移植物中导致肿瘤生长抑制、EGFR蛋白表达抑制和细胞凋亡率增加（程序性细胞死亡）。持续的抗肿瘤效果观察到长达2周后，治疗仅仅停止，结论：这些结果表明，干扰EGFR表达，使用反义为基础的基因治疗方法，可能是一种有效的手段治疗EGFR过度表达的肿瘤，包括SCCHN。
Background: Squamous cell carcinomas of the head and neck (SCCHN), unlike normal mucosal squamous epithelial cells, overexpress epidermal growth factor receptor (EGFR) messenger RNA and protein, EGFR protein is required to sustain the proliferation of SCCHN cells in vitro. To determine whether EGFR expression contributes to tumor growth, me investigated the effect of suppressing EGFR expression in tumor xenografts through in situ expression of antisense oligonucleotides, Methods: Intratumoral cationic liposome-mediated gene transfer was used to deliver plasmids capable of expressing sense or antisense EGFR sequences into human head and neck tumors, which were grown as subcutaneous xenografts in nude mice. The oligonucleotides were expressed under the control of the U6 RNA promoter. Results: Direct inoculation of the EGFR antisense (but not the corresponding sense) plasmid construct into established SCCHN xenografts resulted in inhibition of tumor growth, suppression of EGFR protein expression, and an increased rate of apoptosis (programmed cell death). Sustained antitumor effects were observed for up to 2 weeks after the treatments mere discontinued, Conclusion: These results suggest that interference with EGFR expression, using an antisense-based gene therapy approach, may be an effective means of treating EGFR-overexpressing tumors, including SCCHN.