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Combined treatment, based on lysomustine administration with mesenchymal stem cells expressing cytosine deaminase therapy, leads to pronounced murine Lewis lung carcinoma growth inhibition
Author(s) -
Krassikova Lyudmila S.,
Karshieva Saida S.,
Cheglakov Ivan B.,
Belyavsky Alexander V.
Publication year - 2016
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.2894
Subject(s) - cytosine deaminase , lewis lung carcinoma , mesenchymal stem cell , biology , transplantation , genetic enhancement , microbiology and biotechnology , cancer research , cancer , medicine , biochemistry , gene , genetics , metastasis
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.