Therapeutic properties of a vector carrying the HSV thymidine kinase and GM-CSF genes and delivered as a complex with a cationic copolymer.

Autor: Alekseenko IV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. irina.alekseenko@mail.ru.; Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov Sq. 2, Moscow, 123182, Russia. irina.alekseenko@mail.ru., Snezhkov EV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. cell6370@yandex.ru., Chernov IP; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. igor.palich@gmail.com., Pleshkan VV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. vpleshkan@gmail.com.; Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov Sq. 2, Moscow, 123182, Russia. vpleshkan@gmail.com., Potapov VK; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. vk@ibch.ru., Sass AV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. avsass@mail.ru., Monastyrskaya GS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. gal44.ibch@gmail.com., Kopantzev EP; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. kopantzev@ibch.ru., Vinogradova TV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. vintv56@gmail.com., Khramtsov YV; Institute of Gene Biology, Russian Academy of Sciences, ul. Vavilova, 34/5, Moscow, 119334, Russia. ykhram2000@mail.ru., Ulasov AV; Institute of Gene Biology, Russian Academy of Sciences, ul. Vavilova, 34/5, Moscow, 119334, Russia. al.ulasov@gmail.com., Rosenkranz AA; Institute of Gene Biology, Russian Academy of Sciences, ul. Vavilova, 34/5, Moscow, 119334, Russia. aar@igb.ac.ru.; Moscow State University, Biological Faculty, ul. Leninskiye Gory, 1-12, Moscow, 119234, Russia. aar@igb.ac.ru., Sobolev AS; Institute of Gene Biology, Russian Academy of Sciences, ul. Vavilova, 34/5, Moscow, 119334, Russia. alsobolev@yandex.ru.; Moscow State University, Biological Faculty, ul. Leninskiye Gory, 1-12, Moscow, 119234, Russia. alsobolev@yandex.ru., Bezborodova OA; Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. olgabezborodova@yandex.ru., Plyutinskaya AD; Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. nestor2013@yandex.ru., Nemtsova ER; Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. nemtz@yandex.ru., Yakubovskaya RI; Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. raisayakub@yandex.ru., Sverdlov ED; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. edsverd@gmail.com.; Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov Sq. 2, Moscow, 123182, Russia. edsverd@gmail.com.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2015 Mar 04; Vol. 13, pp. 78. Date of Electronic Publication: 2015 Mar 04.
DOI: 10.1186/s12967-015-0433-0
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Databáze: MEDLINE
Externí odkaz: