FUNDAMENTALS AND PROBLEMS OF SUICIDE GENE ANTITUMOR THERAPY

DOI: https://doi.org/10.29296/24999490-2018-06-03

E.R. Nemtsova, O.A. Bezborodova, R.I. Yakubovskaya, A.D. Kaprin Moscow Hertsen Research Institute of Oncology – branch of National Medical Research Centre of Radiology, 2nd Botkinskiy pr., 3, Moscow, 125284, Russian Federation E-mail: [email protected]

The review of the literature on suicide gene therapy is presented. The therapeutic method is based on the transfection of tumor cells with a construct including the gene of the enzyme converting the substrate – the prodrug demonstrating low toxicity into a highly toxic antitumor agent. Various contemporary data is reviewed in the article concerning gene-therapeutic systems for the treatment: the demands to gene constructs (the genes and promoters), as well as to the substrates (the prodrugs). The most promising delivery systems, both viral and non-viral, are described. The conditions for realization of «bystander effect» – the mechanism enhancing the efficacy of antitumor and antimetastatic effects are considered. The data on the clinical trials of the most thoroughly studied systems «herpes simplex virus thymidine kinase – gancyclovir» and «cytosine deaminase – 5-fluorocytosine» is also reviewed. The results of the authors’ research are also presented. They concern the in vitro and in vivo investigations of the bicistronic construct with the genes of herpes simplex virus thymidine kinase and granulocyte-macrophage colony-stimulating factor under the constitutive cytomegalovirus promoter. Non-viral vector – the block copolymer of the polyethyleneimine and polyethylene glycol with attached TAT-peptide has been used as a delivery system for this construct. The production of the enzyme and cytokine in the transfected cells, the cytotoxic and antitumor effect of the «herpes simplex virus thymidine kinase – gancyclovir» system in various «in vitro» and «in vivo» models, and safety of the system have been proved.
Keywords: 
suicide gene antitumor therapy, viral vector, non-viral vector

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