title: Combined treatment, based on lysomustine administration with mesenchymal stem cells expressing cytosine deaminase therapy, leads to pronounced murine Lewis lung carcinoma growth inhibition.
abstract: BACKGROUND
  The combination of stem cell-based gene therapy with chemotherapy comprises an advantageous strategy that results in a reduction of system toxicity effects and an improvement in the general efficacy of treatment. In the present study, we estimated the efficacy of adipose tissue-derived mesenchymal stem cells (AT-MSCs) expressing cytosine deaminase (CDA) combined with lysomustine chemotherapy in mice bearing late stage Lewis lung carcinoma (LLC).
  
  
  METHODS
  Adipose tissue-derived mesenchymal stem cells were transfected with non-insert plasmid construct transiently expressing fused cytosine deaminase-uracil phosphoribosyltransferase protein (CDA/UPRT) or the same construct fused with Herpes Simplex Virus Type1 tegument protein VP22 (CDA/UPRT/VP22). Systemic administration of 5-fluorocytosine (5FC) and lysomustine was implemented after a single intratumoral injection of transfected AT-MSCs.
  
  
  RESULTS
  We demonstrated that direct intratumoral transplantation of AT-MSCs expressing CDA/UPRT or CDA/UPRT/VP22 followed by systemic administration of 5FC resulted in a significant tumor growth inhibition. There was a 56% reduction in tumor volume in mice treated by AT-MSCs-CDA/UPRT + 5FC or with AT-MSCs-CDA/UPRT/VP22 + 5FC compared to control animals grafted with lung carcinoma alone. Transplantation of AT-MSCs-CDA/UPRT + 5FC and AT-MSCs-CDA/UPRT/VP22 + 5FC prolonged the life span of mice bearing LLC by 27% and 31%, respectively. Co-administration of lysomustine and AT-MSCs-CDA/UPRT + 5FC led to tumor growth inhibition (by 86%) and life span extension (by 60%) compared to the control group.
  
  
  CONCLUSIONS
  Our data indicate that a combination CDA/UPRT-expressing AT-MSCs with lysomustine has a superior antitumor effect in the murine lung carcinoma model compared to monotherapies with transfected AT-MSCs or lysomustine alone, possibly because of a synergistic effect of the combination therapy. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Pushchino State Institute of Natural Sciences, Pushchino, Russia. l.krassikova@gmail.com.|Engelhardt Institute of Molecular Biology RAS, Moscow, Russia. l.krassikova@gmail.com.
authors.forename: Lyudmila S
authors.initials: LS
authors.lastname: Krassikova
authors.affiliation: Engelhardt Institute of Molecular Biology RAS, Moscow, Russia.|N. N. Blokhin Cancer Research Center, Russia.
authors.forename: Saida S
authors.initials: SS
authors.lastname: Karshieva
authors.affiliation: Engelhardt Institute of Molecular Biology RAS, Moscow, Russia.|N. N. Blokhin Cancer Research Center, Russia.
authors.forename: Ivan B
authors.initials: IB
authors.lastname: Cheglakov
authors.affiliation: Engelhardt Institute of Molecular Biology RAS, Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Belyavsky
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009607:Nitrosourea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: D009607:Nitrosourea Compounds; C552857:lysomustine; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase
keywords: Lewis lung carcinoma; cytosine deaminase; lysomustine; mesenchymal stem cells; suicide gene therapy