Alekseenko Irina V, Snezhkov Eugene V, Chernov Igor P, Pleshkan Victor V, Potapov Victor K, Sass Alexander V, Monastyrskaya Galina S, Kopantzev Eugene P, Vinogradova Tatyana V, Khramtsov Yuri V, Ulasov Alexey V, Rosenkranz Andrey A, Sobolev Alexander S, Bezborodova Olga A, Plyutinskaya Anna D, Nemtsova Elena R, Yakubovskaya Raisa I, Sverdlov Eugene D
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia.
Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov Sq. 2, Moscow, 123182, Russia.
J Transl Med. 2015 Mar 4;13:78. doi: 10.1186/s12967-015-0433-0.
Gene-directed enzyme prodrug therapy (GDEPT) represents a technology to improve drug selectivity for cancer cells. It consists of delivery into tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. Major limitations of GDEPT that hinder its clinical application include inefficient delivery into cancer cells and poor prodrug activation by suicide enzymes. We tried to overcome these constraints through a combination of suicide gene therapy with immunomodulating therapy. Viral vectors dominate in present-day GDEPT clinical trials due to efficient transfection and production of therapeutic genes. However, safety concerns associated with severe immune and inflammatory responses as well as high cost of the production of therapeutic viruses can limit therapeutic use of virus-based therapeutics. We tried to overcome this problem by using a simple nonviral delivery system.
We studied the antitumor efficacy of a PEI (polyethylenimine)-PEG (polyethylene glycol) copolymer carrying the HSVtk gene combined in one vector with granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA. The system HSVtk-GM-CSF/PEI-PEG was tested in vitro in various mouse and human cell lines, ex vivo and in vivo using mouse models.
We showed that the HSVtk-GM-CSF/PEI-PEG system effectively inhibited the growth of transplanted human and mouse tumors, suppressed metastasis and increased animal lifespan.
We demonstrated that appreciable tumor shrinkage and metastasis inhibition could be achieved with a simple and low toxic chemical carrier - a PEI-PEG copolymer. Our data indicate that combined suicide and cytokine gene therapy may provide a powerful approach for the treatment of solid tumors and their metastases.
基因导向酶前药疗法（GDEPT）是一种提高药物对癌细胞选择性的技术。它包括将一个自杀基因导入肿瘤细胞，该基因负责将前药原位转化为细胞毒性代谢物。阻碍GDEPT临床应用的主要限制包括癌细胞摄取效率低和自杀酶对前药的激活效果差。我们试图通过将自杀基因疗法与免疫调节疗法相结合来克服这些限制。由于治疗基因的高效转染和生产，病毒载体在当今GDEPT临床试验中占主导地位。然而，与严重免疫和炎症反应相关的安全问题以及治疗性病毒生产成本高昂，可能会限制基于病毒的治疗方法的治疗应用。我们试图通过使用简单的非病毒递送系统来克服这个问题。
我们研究了一种携带单纯疱疹病毒胸苷激酶（HSVtk）基因并与粒细胞巨噬细胞集落刺激因子（GM-CSF）cDNA组合在一个载体中的聚乙烯亚胺（PEI）-聚乙二醇（PEG）共聚物的抗肿瘤疗效。HSVtk-GM-CSF/PEI-PEG系统在体外的各种小鼠和人类细胞系中、离体以及使用小鼠模型在体内进行了测试。
我们表明HSVtk-GM-CSF/PEI-PEG系统有效地抑制了移植的人类和小鼠肿瘤的生长，抑制了转移并延长了动物寿命。
我们证明了使用一种简单且低毒的化学载体——PEI-PEG共聚物，可以实现明显的肿瘤缩小和转移抑制。我们的数据表明，联合自杀基因和细胞因子基因疗法可能为实体瘤及其转移的治疗提供一种强大的方法。
