Xu L, Pirollo K F, Chang E H
Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
J Control Release. 2001 Jul 6;74(1-3):115-28. doi: 10.1016/s0168-3659(01)00324-8.
A long-standing goal in gene therapy for cancer is a stable, low toxic, systemic gene delivery system that selectively targets tumor cells, including metastatic disease. Progress has been made toward developing non-viral, pharmaceutical formulations of genes for in vivo human therapy, particularly cationic liposome-mediated gene transfer systems. Ligand-directed tumor targeting of cationic liposome-DNA complexes (lipoplexes) is showing promise for targeted gene delivery and systemic gene therapy. Lipoplexes directed by ligands such as folate, transferrin or anti-transferrin receptor scFv, showed tumor-targeted gene delivery and expression in human breast, prostate, head and neck cancers. The two elements, ligand/receptor and liposome composition, work together to realize the goal of functional tumor targeting of gene therapeutics. The tumor suppressor gene, p53, has been shown to be involved in the control of DNA damage-induced apoptosis. Loss or malfunction of this p53-mediated apoptotic pathway has been proposed as one mechanism by which tumors become resistant to chemotherapy or radiation. The systemically delivered ligand-liposome-p53 gene therapeutics resulted in efficient expression of functional wild-type p53, sensitizing the tumors to chemotherapy and radiotherapy. This is a novel strategy combining current molecular medicine with conventional chemotherapy and radiotherapy for the treatment of cancer. The systemic delivery of normal tumor suppressor gene p53 by a non-viral, tumor-targeted delivery system as a new therapeutic intervention has the potential to critically impact the clinical management of cancer.
癌症基因治疗的一个长期目标是构建一个稳定、低毒的全身基因递送系统，该系统能够选择性地靶向肿瘤细胞，包括转移性疾病。在开发用于体内人类治疗的非病毒基因药物制剂，特别是阳离子脂质体介导的基因转移系统方面已经取得了进展。阳离子脂质体-DNA复合物（脂质体复合物）的配体导向肿瘤靶向在靶向基因递送和全身基因治疗方面显示出前景。由叶酸、转铁蛋白或抗转铁蛋白受体单链抗体等配体导向的脂质体复合物，在人类乳腺癌、前列腺癌、头颈癌中显示出肿瘤靶向基因递送和表达。配体/受体和脂质体组成这两个要素共同作用，以实现基因治疗功能性肿瘤靶向的目标。肿瘤抑制基因p53已被证明参与DNA损伤诱导的细胞凋亡的控制。这种p53介导的凋亡途径的缺失或功能障碍被认为是肿瘤对化疗或放疗产生抗性的一种机制。全身递送的配体-脂质体-p53基因治疗剂导致功能性野生型p53的有效表达，使肿瘤对化疗和放疗敏感。这是一种将当前分子医学与传统化疗和放疗相结合治疗癌症的新策略。通过非病毒、肿瘤靶向递送系统全身递送正常肿瘤抑制基因p53作为一种新的治疗干预措施，有可能对癌症的临床管理产生重大影响。
