Rocco J W, Li D, Liggett W H, Duan L, Saunders J K, Sidransky D, O'Malley B W
Department of Otolaryngology and Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University, Baltimore, Maryland 21203-6402, USA.
Clin Cancer Res. 1998 Jul;4(7):1697-704.
Inactivation of the tumor suppressor gene p16INK4A is the most common genetic alteration in human head and neck squamous cell cancer (HNSCC), making it an ideal target for gene replacement. We constructed a replication-defective, recombinant adenovirus capable of directing a high level of p16INK4A protein expression (Ad5-p16) to investigate its benefit in treating HNSCC. Initial in vitro experiments in four human HNSCC cell lines demonstrated that Ad5-p16 treatment significantly inhibits cell growth with up to 96% efficiency. Flow cytometric analysis showed that Ad5-p16 induced a maximum G1-S cell cycle arrest of 90%. Subsequent studies in a nude mouse model demonstrated that Ad5-p16 treatment significantly reduced (cell line 011) or stabilized (cell line 012) established tumors when compared with control treatments (P < 0.008). These results demonstrate for the first time a significant antitumor effect of Ad5-p16 against human HNSCC in vivo and support the potential application of Ad5-p16 to treat locally advanced, unresectable, or metastatic head and neck cancer, as well as microscopic residual disease after surgical resection.
肿瘤抑制基因p16INK4A的失活是人类头颈部鳞状细胞癌（HNSCC）中最常见的基因改变，使其成为基因替代的理想靶点。我们构建了一种复制缺陷型重组腺病毒，能够指导高水平的p16INK4A蛋白表达（Ad5-p16），以研究其在治疗HNSCC中的益处。在四种人类HNSCC细胞系中进行的初步体外实验表明，Ad5-p16治疗可显著抑制细胞生长，效率高达96%。流式细胞术分析显示，Ad5-p16诱导的G1-S期细胞周期阻滞最大可达90%。随后在裸鼠模型中的研究表明，与对照治疗相比，Ad5-p16治疗可显著缩小已形成的肿瘤（011细胞系）或使其稳定（012细胞系）（P < 0.008）。这些结果首次证明了Ad5-p16在体内对人类HNSCC具有显著的抗肿瘤作用，并支持Ad5-p16在治疗局部晚期、不可切除或转移性头颈部癌以及手术切除后的微小残留疾病方面的潜在应用。
