NK 4 Gene Therapy Combined with Cisplatin Inhibits Tumour Growth and Metastasis of Squamous Cell Carcinoma-猫眼课题宝

DOI：

发表时间：

2011

期刊：

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

G. Matsumoto;Yasushi Omi;U. Lee;E. Kubota;Y. Tabata

背景：NK 4抑制肿瘤组织中的血管形成，从而阻止肿瘤生长。然而，体内表达的单个抗血管生成分子的抗肿瘤功效不足以在动物模型中诱导消退。克服这一缺点的策略之一是使用化疗。材料和方法：本研究旨在评价NK 4基因治疗联合顺铂治疗实验性鳞状细胞癌的疗效。对于基因治疗，可生物降解的阳离子化明胶微球用于控制释放NK 4质粒DNA。结果如下：抗血管生成基因治疗和低剂量顺铂的联合方案导致肿瘤体积和血管分布显著减少，并导致细胞凋亡增加相比，单独的NK 4基因治疗。此外，NK 4基因治疗和低剂量顺铂的联合治疗显著抑制肺转移的形成。结论：NK 4基因联合小剂量顺铂治疗口腔鳞癌可能是一种有效的治疗方案。口腔鳞状细胞癌生长迅速，即使经过积极的化疗、放疗和/或手术治疗，也经常复发。这种疾病的特点是迅速侵入骨骼和肌肉，并有高度的新生血管。仅口腔和咽部的癌症就占全球每年30多万新发病例和近20万例死亡（1）。特别是舌是口腔肿瘤最常见的部位;在过去的25年中，舌癌患者的5年生存率没有改善，仍然低于50%（2）。舌癌的预后不良可能反映了对局部和区域转移机制的认识有限，占死亡的大多数。因此，需要开发新的治疗策略，特别是那些抓住基因治疗优势的策略。头颈部鳞状细胞癌的几种基因治疗策略目前正在临床和临床前研究中（3，4）。新血管形成过程由肿瘤细胞诱导，肿瘤细胞通常刺激内皮细胞增殖和分化（5）。在某些肿瘤中，开启新血管形成过程需要上调血管生成刺激因子和下调血管生成抑制因子（6）。相反，几种抗血管生成因子抑制已从原发肿瘤部位释放到循环系统中的转移性细胞的生长。HGF是肝细胞生长的有效刺激剂，可刺激上皮细胞的运动性、侵袭性、增殖和形态发生，并可能在生理和病理过程中发挥作用，如胚胎发生、伤口愈合、器官再生、炎症和肿瘤侵袭（7）。据报道，HGF可能在下咽鳞状细胞癌的进展中起重要作用（8）。已经制备了一种称为NK 4的特异性HGF拮抗剂，其与c-Met/HGF受体结合，而不诱导c-Met的酪氨酸磷酸化。据报道，NK 4可抑制HGF、bFGF和VEGF诱导的血管生成反应（9）。通过NK 4阻断HGF/c-Met偶联可抑制肿瘤细胞的侵袭、运动和随后的内渗，从而抑制肺转移。为了提高表达质粒DNA的生物学活性，必须提高其对细胞的体内转染效率。由于质粒DNA是一个大的带负电荷的分子，即使它附着在带负电荷的细胞膜上，也不能进入细胞内部。由于明胶易于应用于工业、制药和医疗领域，因此明胶已被广泛应用于工业、制药和医疗领域。电话/传真：+81 468228895，邮箱：oslab@kdcnet.ac.jp

Background: NK4 inhibits vascularisation in tumour tissues, thereby arresting tumour growth. However, the antitumour efficacy of individual antiangiogenic molecules expressed in vivo is not sufficiently potent to induce regression in animal models. One of the strategies to overcome this disadvantage is to use chemotherapy. Materials and Methods: This study evaluated the efficacy of combining NK4 gene therapy with cisplatin to treat experimental squamous cell carcinomas. For gene therapy, biodegradable cationised gelatin microspheres were used for the controlled release of NK4 plasmid DNA. Results: A combined regimen of antiangiogenic gene therapy and lowdose cisplatin led to a marked decrease in tumour volume and vascularity, and caused increased apoptosis compared to NK4 gene therapy alone. Moreover, combination treatment of NK4 gene therapy and low-dose cisplatin dramatically inhibited the formation of lung metastases. Conclusion: NK4 gene therapy combined with low-dose cisplatin may be an effective regimen for treating oral squamous cell carcinoma. Oral squamous cell carcinomas grow rapidly, and they often recur, even after they have been treated aggressively with chemotherapy, radiation and/or surgery. The disease is characterized by a rapid invasion into bone and muscle and a high degree of neovascularity. Cancers of the oral and pharynx regions alone account for over 300,000 new cases worldwide and almost 200,000 deaths annually (1). The tongue in particular is the most common site for tumours of the oral cavity; the 5-year survival rates for patients treated for tongue carcinoma have not improved in the past 25 years and remain less than 50% (2). The poor prognosis for tongue carcinoma may reflect a limited understanding of the mechanisms of local and regional metastasis, accounting for the majority of deaths. Therefore, new treatment strategies need to be developed, especially those that capture the advantages of gene therapy. Several gene therapy strategies for head and neck squamous cell carcinoma are currently under investigation in clinical and preclinical settings (3, 4). The neovascularisation process is induced by tumour cells, which normally stimulate endothelial cells to proliferate and differentiate (5). Turning on the neovascularisation process requires both the up-regulation of angiogenic stimulators and the down-regulation of angiogenic inhibitors in certain tumours (6). In contrast, several antiangiogenic factors suppress the growth of metastatic cells that have been released into the circulatory system from a primary tumour site. HGF, a potent stimulator of hepatocyte growth, stimulates the motility, invasiveness, proliferation and morphogenesis of the epithelium and may play a role in physiological and pathological processes such as embryogenesis, wound healing, organ regeneration, inflammation, and tumour invasion (7). It has been reported that HGF may play an important role in the progression of hypopharyngeal squamous cell carcinoma (8). A specific HGF-antagonist termed NK4 has been prepared and binds to the c-Met/HGF receptor, without inducing tyrosine phosphorylation of c-Met. It has been reported that NK4 may inhibit the angiogenic responses induced by HGF, bFGF and VEGF (9). The blockade of HGF/c-Met coupling by NK4 may suppress the invasion, motility and subsequent intravasation of tumour cells, leading to the inhibition of lung metastases. To increase the biological activity of the expressing plasmid DNA, it is necessary to increase its transfection efficiency to cells in vivo. As plasmid DNA is a large and negatively charged molecule, it cannot pass into the interior of cells even if it attaches to the negatively charged cell membrane. Gelatin has been used extensively in industrial, pharmaceutical and medical applications because of the ease 105 Correspondence to: Goichi Matsumoto, Department of Oral and Maxillofacial Surgery, Kanagawa Dental College, 82 Inaoka, Yokosuka, Kanagawa 238-8580, Japan. Tel/Fax: +81 468228895, e-mail: oslab@kdcnet.ac.jp

NK 4 Gene Therapy Combined with Cisplatin Inhibits Tumour Growth and Metastasis of Squamous Cell Carcinoma

文献摘要

相似文献