He Y, Zeng Q, Drenning S D, Melhem M F, Tweardy D J, Huang L, Grandis J R
Department of Pharmacology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, PA, USA.
J Natl Cancer Inst. 1998 Jul 15;90(14):1080-7. doi: 10.1093/jnci/90.14.1080.
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, we investigated the effect of suppressing EGFR expression in tumor xenografts through in situ expression of antisense oligonucleotides.
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.
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 were discontinued.
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.
与正常黏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）信使核糖核酸和蛋白质。EGFR蛋白是体外维持SCCHN细胞增殖所必需的。为了确定EGFR表达是否有助于肿瘤生长，我们通过反义寡核苷酸的原位表达研究了抑制肿瘤异种移植物中EGFR表达的效果。
采用瘤内阳离子脂质体介导的基因转移，将能够表达正义或反义EGFR序列的质粒导入人头部和颈部肿瘤，这些肿瘤在裸鼠体内作为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。
将EGFR反义（而非相应正义）质粒构建体直接接种到已建立的SCCHN异种移植物中，导致肿瘤生长受到抑制、EGFR蛋白表达受到抑制以及凋亡（程序性细胞死亡）率增加。在治疗停止后长达2周内观察到持续的抗肿瘤作用。
这些结果表明，使用基于反义的基因治疗方法干扰EGFR表达，可能是治疗包括SCCHN在内的EGFR过表达肿瘤的有效手段。
