Department of Pharmacy, Pharmaceutical Biotechnology, Center for System based Drug Research, Ludwig Maximilians University, Munich, Germany.
Mol Ther. 2013 Feb;21(2):300-8. doi: 10.1038/mt.2012.229. Epub 2012 Nov 13.
Tumor necrosis factor alpha (TNFα) is a potent antitumoral cytokine, either killing tumor cells directly or affecting the tumor vasculature leading to enhanced accumulation of macromolecular drugs. Due to dose limiting side effects systemic administration of TNFα protein at therapeutically active doses is precluded. With gene vectors, tumor restricted TNFα expression can be achieved and in principle synergize with chemotherapy. Synthetic gene carriers based on polyamines were intravenously injected, which either passively accumulate within the tumor or specifically target the epidermal growth factor receptor. A single intravenous injection of TNFα gene vector promoted accumulation of liposomal doxorubicine (Doxil) in murine neuroblastoma and human hepatoma by enhancing tumor endothelium permeability. The expression of transgenic TNFα was restricted to tumor tissue. Three treatment cycles with TNFα gene vectors and Doxil significantly delayed tumor growth in subcutaneous murine Neuro2A neuroblastoma. Also tumors re-growing after initial treatment were successfully treated in a fourth cycle pointing at the absence of resistance mechanisms. Systemic Neuro2A metastases or human LS174T colon carcinoma metastases in liver were also successfully treated with this combined approach. In conclusion, this schedule opens the possibility for the efficient treatment of tumors metastases otherwise not accessible for macromolecular drug carriers.
肿瘤坏死因子-α（TNFα）是一种有效的抗肿瘤细胞因子，它可以直接杀伤肿瘤细胞，或影响肿瘤血管系统，导致大分子药物的蓄积增强。由于全身给药会产生剂量限制的副作用，因此不能用 TNFα 蛋白进行治疗剂量的全身给药。利用基因载体，可以实现肿瘤局限的 TNFα 表达，并与化疗协同作用。基于聚胺的合成基因载体被静脉内注射，这些载体可以被动地在肿瘤内蓄积，或者特异性地靶向表皮生长因子受体。单次静脉注射 TNFα 基因载体通过增强肿瘤内皮通透性，促进脂质体阿霉素（Doxil）在鼠神经母细胞瘤和人肝癌中的蓄积。转基因 TNFα 的表达局限于肿瘤组织。用 TNFα 基因载体和 Doxil 进行三次治疗周期，显著延缓了皮下鼠源性神经母细胞瘤 Neuro2A 的肿瘤生长。在第四次治疗周期中，对初始治疗后重新生长的肿瘤也进行了成功治疗，这表明不存在耐药机制。用这种联合方法还成功治疗了全身性的 Neuro2A 转移瘤或肝内的人 LS174T 结肠癌细胞转移瘤。总之，这种方案为治疗其他大分子药物载体无法到达的肿瘤转移提供了可能。
