Blackwell J L, Miller C R, Douglas J T, Li H, Reynolds P N, Carroll W R, Peters G E, Strong T V, Curiel D T
Department of Medicine, University of Alabama at Birmingham, 35294, USA.
Arch Otolaryngol Head Neck Surg. 1999 Aug;125(8):856-63. doi: 10.1001/archotol.125.8.856.
Adenovirus-mediated gene therapy has been used for squamous cell carcinoma of the head and neck (SCCHN), but the in vivo efficacy has been limited by a lack of tissue specificity and low infection efficiency. We are interested in improving cancer gene therapy strategies using targeted adenovirus vectors.
To determine if the infection efficiency of adenovirus-mediated gene transfer to SCCHN cells could be enhanced by retargeting to the epidermal growth factor receptor (EGFR), which is known to be overexpressed in these tumors.
Epidermal growth factor receptor retargeting in SCCHN cells was accomplished with a bispecific antibody that recognized the knob domain of adenovirus as well as EGFR. Using this retargeting schema, we compared the infection efficiency and specificity of unmodified and EGFR-retargeted adenovirus.
Squamous cell carcinoma of the head and neck cell lines were shown to be infected by adenovirus with low efficiency, which is likely because of the low level of adenovirus receptor expressed in the SCCHN cells. Epidermal growth factor receptor retargeting markedly enhanced transduction in both SCCHN cell lines and primary tumor tissue, as indicated by the elevated levels of reporter gene expression. Furthermore, retargeting enhanced infection of tumor tissue compared with normal tissue from the same patient.
Epidermal growth factor receptor retargeting enhanced adenovirus infection of SCCHN cells and, in doing so, augments the potency of the vector. This modification makes the vector potentially more valuable in the clinical setting.
腺病毒介导的基因治疗已用于头颈部鳞状细胞癌（SCCHN），但其体内疗效受到组织特异性缺乏和感染效率低的限制。我们有兴趣利用靶向腺病毒载体改进癌症基因治疗策略。
确定通过重新靶向表皮生长因子受体（EGFR）（已知在这些肿瘤中过度表达）是否可以提高腺病毒介导的基因转移至SCCHN细胞的感染效率。
使用识别腺病毒的纤突结构域以及EGFR的双特异性抗体在SCCHN细胞中实现表皮生长因子受体重新靶向。使用这种重新靶向方案，我们比较了未修饰的和EGFR靶向的腺病毒的感染效率和特异性。
头颈部鳞状细胞癌细胞系被腺病毒低效感染，这可能是因为SCCHN细胞中腺病毒受体表达水平低。如报告基因表达水平升高所示，表皮生长因子受体重新靶向显著增强了两种SCCHN细胞系和原发性肿瘤组织中的转导。此外，与同一患者的正常组织相比，重新靶向增强了肿瘤组织的感染。
表皮生长因子受体重新靶向增强了腺病毒对SCCHN细胞的感染，从而增强了载体的效力。这种修饰使载体在临床环境中可能更有价值。
