title: Therapeutic properties of a vector carrying the HSV thymidine kinase and GM-CSF genes and delivered as a complex with a cationic copolymer.
abstract: 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.
authors.affiliation: 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.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Alekseenko
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. cell6370@yandex.ru.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Snezhkov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. igor.palich@gmail.com.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Chernov
authors.affiliation: 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.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Pleshkan
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. vk@ibch.ru.
authors.forename: Victor K
authors.initials: VK
authors.lastname: Potapov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. avsass@mail.ru.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Sass
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. gal44.ibch@gmail.com.
authors.forename: Galina S
authors.initials: GS
authors.lastname: Monastyrskaya
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. kopantzev@ibch.ru.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Kopantzev
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. vintv56@gmail.com.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Vinogradova
authors.affiliation: Institute of Gene Biology, Russian Academy of Sciences, ul. Vavilova, 34/5, Moscow, 119334, Russia. ykhram2000@mail.ru.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Khramtsov
authors.affiliation: Institute of Gene Biology, Russian Academy of Sciences, ul. Vavilova, 34/5, Moscow, 119334, Russia. al.ulasov@gmail.com.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ulasov
authors.affiliation: 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.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Rosenkranz
authors.affiliation: 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.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Sobolev
authors.affiliation: Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. olgabezborodova@yandex.ru.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Bezborodova
authors.affiliation: Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. nestor2013@yandex.ru.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Plyutinskaya
authors.affiliation: Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. nemtz@yandex.ru.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Nemtsova
authors.affiliation: Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, 2nd Botkinskiy proezd 3, Moscow, 125284, Russia. raisayakub@yandex.ru.
authors.forename: Raisa I
authors.initials: RI
authors.lastname: Yakubovskaya
authors.affiliation: 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.
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Sverdlov
mesh_terms: D000818:Animals; D002412:Cations; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000235:genetics; D008055:Lipids; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics* / Q000627:therapeutic use*
chemical_list: D002412:Cations; D000067556:Internal Ribosome Entry Sites; D008055:Lipids; C086724:Lipofectamine; D011108:Polymers; D011092:Polyethylene Glycols; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011094:Polyethyleneimine; D013937:Thymidine Kinase; D015774:Ganciclovir